ContentsPolyanion water activity regulation &
Preliminary notes dealing with the enthalpy-entropy compensation
effect0. Sub-transition state free energy flow chanelling may
generate enthalpy entropy compensation01. The isokinetic
temperature phenomenon may give rise to stochastic structural
reorganization phenomena 02. 03. Chemical affinity re-defined for
stochastic chemical reactivityThe Fluctuation Theorem suggests that
F (rather than F) is the chemical affinity in compensated
systems
1. Brownian Motion2. Biological Nucleation 3. Compensation
effects elucidate water structure
4. Liu & Guo (2001) Review5. Aberdeen U. (1984) Review
6. Putative Time Reversal & Compressed Time 7. Coveney
(1988) Review 8. Vacuum Space and Extrathermodynamic Phenomena 9.
Reverse Entropy & Vacuum Space 10. Vacuum Time 11., 12
Dehydrochlorination compensation data etc. 13 Redefining the nature
of chemical reactivity 14. Soubility & Nucleation 14a.
Nucleaton inhibitors
---------------------------------------------------------------------------------15.
Van Wazer structural reorgnization
------------------------------------------------------------------------------16.
(Heparan Sulfate & Degenerative Diseases) Mss. ex University of
Aberdeen, Etc.
Manuscript POLYANION WATER ACTIVITY REGULATION A Hypothesis:
Heparin/Heparan Sulphates Modulate Protein Activities by Water
Activity Regulation Including Nanohole Induced Non-Equilibrium
Water and Hofmeister-Like Effects Generated by Interfacial Aqueous
Phases with High Ionic Strength, Multi-Element Inorganic Salt
Compositions David Grant PhD MRSC* Aberdeenshire UK AB53 6SX (&
University of Aberdeen) Heparan sulphate microstructure, evidently
strictly regulated both temporarily and positionally during
development (being responsible amongst numerous other established
functions for regulating several growth factor activities [(1) cf.
Bernfield et al. 1999; Hacker et al 2005] which are apparently
dependent on the existence in syndecans, glypicans, agrin and other
protoglycans of heparan sulphate sidechains having a great variety
different linearly information-encoded sequences (dependent on the
occurrence in this uronic acid (1->4) D glucosamine repeat
disaccharides of sulphated iduronate, glucouronate and N acetyl,
N-sulphonate or unsubstituted glucosamine 2-deoxyglucosamine,
residues) which are believed to enable several types of signalling
including those involving binding to basic sites
in proteins via specific information encoded sequences of sugars
analogous to the pentasaccharide antithrombin-binding site heparin
(Bernfield et al 1999; Lyon & Gallagher 1997) (such an
information code is more complex than that of DNA to which it is
obviously is however similar in principle although the heparan
sulphate system apparently lacks any ability to act as a template
for its self replication). It is now further suggested that binding
of polysaccharides to proteins may require correct interstitial
aqueous solutions (e.g. containing separate soft-ice like phases)
which are now believed to contribute to the inorganic co-solute
multi-ionic environments** . With heparan sulphate it seems that a
system other than molecular recognition by an antithrombin
(AT)-like-fine tuned electrostatic quaternary N+ protein link to
individual codon sulphate mineral-like anionic patterns must allow
fine structure discrimination to be established. A required high
degree of selectivity by different microstructures present in
different heparan sulphates seems to be the basis for their ability
to select different proteins for their normal (e.g. growth factor
orchestration) functions. The existence of some previously
unsuspected unconventional molecular recognition system is however
apparently required to facilitate this. This possibility is
suggested by the work of Kreuger et al 2005) who found that most
probable signalling oligosaccharides failed to discriminate between
their individual FGF growth factor isoforms target binding sites
when they were present as individual molecular signals (obtained
from the high molecular weight by scission, separation and
purification) . This finding is starkly contrary to the selectivity
apparently achieved by the parent high molecular weigh
proteoglycans in their in vivo environments. This situation might
have arisen (as suggested by Kreuger et al) from the ability of
such larger molecules (but not the smaller segments) to form
additional hydrogen-bonding, Van der Waals forces and salt links
(including those with inorganic ion bridges) and perhaps involving
the whole heparan sulphate proteoglycan chain which may be
involved. It is now proposed that the ultimate basis of heparan
sulphate signalling is actually the induced water structure (e.g.
this is acknowledged to be promoted in some non-specific manner by
the extracellular matrix) and that this is the ultimate cause of
tissue integrity. Tissue development may also require input form
correct water structures associated with the longer polysaccharide
segments molecules. This correct water structure for the proposed
heparan sulphate signalling etc. functions could involve both
hydrophilic and hydrophobic repulsive and attractive forces similar
to the often long range effects which have been identified to occur
in aqueous solutions between hydrophobic surfaces and hydrophobic
and hydophilic mica surfaces (cf. Christenson & Claesson 2001)
for which such long range effects have been identified might
conceivably mimic the high anionic density + hydrophobic N-Ac
region systems of heparan sulphates). These types of water
structures are also believed to critically depend on the presence
of sub-microscopic sized nano holes which have been in water
structures (micro-bubbles) (e.g. adjacent to mica and silicate
surface studies by atomic force microscopy) pointing to the
possible key role of such a mechanism in the of formation of
(presumable non-equilibrium, thermostatically unstable) water
microstructures in the biochemical mechanism of tissue generation
and its upkeep. Myelin basic protein integrity may depend on the
hydrophobic effect on water structure and depend on microbubbles
for its existence as it is associated with lipid induced
hydrophobic waters structuring effects (Muelle et al 1999). It
should be noted that the integrity of this protein has also been
associated with heparan sulphate proteoglycans which enable the
repair of damaged myelin sheaths, defects in which can be argued to
give rise to neurological conditions such as multiple sclerosis. A
scenario by which is this process becomes disrupted by a UV-vitamin
D-thyroid factor dependent sulphate transporter which facilitates
heparan sulphate sulphation could explain the geographical
incidence of multiple sclerosis in Australia and perhaps also the
possible promotion of this disease by barium intoxication (Purdey,
2004). It can also be logically suggested (e.g. Dr 2008) that
protein folding must depend largely on the existence and the
activities of interstitial water; The Hofmeister series can be
explained by the effects of high concentrations of protein
stabilisers or denaturant solutes on the surface tension of the
interfacial water. This concept should also be extended it is now
proposed to include the effect of nanobubbles on water structure.
Since heparin and heparin-like sites in heparan sulphate are
ultra-anionic, high ionic strength co-solute generating
environments to those which promote the Hofmeister effect, it is
also expected that the interstitial water which occurs adjacent to
heparin/heparan sulphate polysaccharides could likewise
generate local Hofmeister effects which could determine how
heparan sulphate attaches to and alters the conformation of target
proteins. Direct evidence that such interstitial water might
participates in such actions was obtained from studies of the
binding of heparin to poly-L-lysine and poly-L-arginine (Grant et
al. 1991) which indicated that such binding was accompanied by
large changes in the overtone stretching frequencies of the water
molecules attached to heparin. Related studies by these authors of
the binding of inorganic ions and inorganic solids to heparin** and
heparan sulphate tended to confirm that such binding depended on
hydration changes (rather than electrostatic attractive forces,
e.g. as had previously been believed to control this activity (cf.
the Manning hypothesis). Related studies by the same authors that
interstitial water and entropy changes thereof also apparently
determined how a range of inorganic counterions bound to heparin.
Further direct evidence for the existence of a high ionic strength
environment adjacent to heparin is that crystalline akaganeite
fibers (identified by X-ray diffractions) are produced at heparin
surfaces (following binding of Fe2+ to heparin, its oxidation to
Fe3+ Co2+ - dependent (such ions were also apparently commonly
co-purified with heparin). [Formation of this fibrillar crystalline
material {FeO.OH} is known to require the high ionic strength
conditions]; (Williamson FB Aberdeen, personal communication of
unpublished work). Biological Fluids are Seawater-Like Multielement
Matrices from which Heparin and Anionic Polysaccharides Selectively
Sequester the Least Abundant Solute Ions. In an internet paper
(which is now no longer accessible) which discussed how water
structure influences protein folding G Wilse Robinson quoted Szengt
Gorgi who had earlier pointed out that humans are essentially bags
of skin filled with seawater. Haraguchi, (2004) included heparin in
his tabulation of topics for which a suggested that the new science
of metallomics [a concept which had earlier been introduced by RJP
Williams] which deals with the multi-inorganic nature of geological
and biological phenomena including the seawater range of inorganic
elements, which should be potentially be considered of fundamental
importance to biochemistry since biological fluids are
multi-inorganic ion solutions which are usually approximately
similar in their multi-inorganic element compositions to seawater
and other natural waters. It might further be suggested that since
heparan sulphate seems to have co-evolved with multicellular
animals in the sea some 109 years ago a primitive role of cell
surface heparan sulphates was to act as a nutrient gatherer and
buffer for bio-friendly seawater-like multi inorganic element
containing salt solutions. This notion seems to be confirmed by a
report from the Dietrich group of the existence of an exact
mathematical relationship (Nader et al. 1983) between the amounts
of tissue heparan sulphates (and other sulphated polysaccharides)
and the salinities of the habitats of fifteen species of aquatic
invertebrates, where habitat water might be required to directly
bathe the heparan -sulphateproteoglycan-lined tissues. Anionic
polysaccharides (and proteins) in animals when bathed in the
multi-inorganic ion salt solution biological fluids will generate
multi-inorganic ion/hydration water complexes similar to the
anionic polysaccharides abundantly present in the cell walls of
marine algae had been established (Wassemannn, 1949) most likely to
exist in this form in vivo rather than being present, as was
originally supposed, as free alginic acid Although less chemically
definable than the pure polyanionc polysaccharides (alginates,
carrageenans, and the polysaccharide side-chains of
glycosaminoglycans etc.) but nevertheless of considerable
importance to the homoeostasis of inorganic ions including
carbonate, bicarbonate and Ca2+ ions in natural waters is the
system of humic/fulvic polymers (a system of polymethylene,
polycarbonyl, caboxylated) material which comprises the largest
system of organic polymers on earth. These natural polyanions bind
numerous metal ions present in seawater etc. via abundant -COO-
groups, which apparently gave rise to the geological deposits of
fulvate organic matter. Determination by spark source mass
spectrometry (SSMS) of the multi-inorganic element contents of
geological fulvates and marine alginate showed obvious qualitative
similarities to the SSMS results for the multi-element contents of
the animal polysaccharide heparin (Grant et al. 1987). Less
information is currently available from the literature of similar
studies of heparan sulphates (which are more difficult to obtain in
large amounts) but studies conducted in the context of scitigraphic
imaging (e.g. of tumours) has indicated that this procedure may
depend upon the binding of the radionuclides to heparan sulphate
proteoglycans e.g. at cell surfaces; side experiments
established that 45Ca in heparan sulphate could be replaced by a
range of multivalent metal counterions in a manner consistent with
heparan sulphate being normally present in vivo in the form of a
multiinorganic matrix. The apparent differences in the observed
biochemical/physical properties of different brands of heparin
seems to at least in part have its origin in the different degrees
of purification achieved by different manufacturers. It might even
be suggested that such attempts at purification actually achieve
inappropriate forms of heparin, at least from the requirement of
biochemical if not from the standpoint of pharmacological research.
What is obviously required for fundamental biochemical researches
is the actual form of polyanions which are present in vivo. That
the achievement of the equilibrium between the polyanion and the
multi-element bathing fluids is not re-established rapidly may be
deduced form the reports that the different single salt forms of
heparin have different in vivo activities. The traditional view was
that the multi-element character of unrefined heparin was of little
scientific interest and that samples used for biochemical
researches should be as free from such multi-elements as possible.
[A similar hypothesis was applied to chitosan research, where the
existence of multielements had been attributed to uptake from a
final washing in tap water]. This idea is suggested to be incorrect
and the status of the inorganic/water co-sphere around anionic
polysaccharides which could potentially be part of an
organometallic signalling system needs to be re-evaluated.
*This hypothesis was generated from private discussions
(including with FB Williamson PhD and Professor WF Long** of the
former University of Aberdeen, Marischal College Polysaccharide
Laboratory, correspondence with Professor RJP Williams , Oxford
University) and extensive internet literature studies made
privately from Ashbank, Turriff AB53 6SX, UK as well as by use of
the facilities kindly provided by Queen Mother Library Kings
College and Forresterhill Medical Library, University of Aberdeen.
**The majority of the published papers of this polysaccharide
research group we posted by Professor WF Long at
http://www/abdn.ac.uk/~bch118/publicatuions2003march.doc References
arranged alphabetically Bernfield M et al 1999, Ann Rev Biochem.
68, DATA72907777; Cf. Hacker U Nybakken K Perrison N Nature Reviews
Molecular Cell Biology 6 530-54- doi: 10.1038/nrm1681 Christenson
HK Claesson PM 2001 Adv Colloid Interface Sci 91 (3) 391-436 Dr A
2008 Salts, interfacial water and protein conformation Biotechnol
& Biotechnol Eq. 22 (1) 629-633 [Cf. Dr A Kelemen L Fbin L
Taneva SG Fodor E Pli T Cupane A Cacace MG Ramsden JJ 2007 J Phys
Chem 111, 5344-5350] Protein folding was traditionally viewed as an
intrinsic property of the amino acid sequence in which the solvent
had a secondary role; inherent hydrophilic/hydrophobic effects were
believed to be directed by the amino acid sequences alone. This
view has recently been challenged. Dr et al re-evaluated how
proteins fold and suggested that the principal influence (or
driving force) for protein folding originates from a dominant
effect of water structure/activity on protein supramolecular
structure/conformation. Such an influence of water structure also
explains the Hofmeister or lyotropic series a phenomenon of protein
denaturation characteristic of high solute (including inorganic
salt) molecule concentrations. [Hofmeister salts change the
hydophobic/hydrophilic properties of protein-water interfaces,
kosmotropes making them more hydrobphobic while chaotropes make
them more hydrophilic (these
terms were used in the context of their surface free energies).
Surface tension*** of salt solutions in air had long been regarded
as being related to the Hofmeister effect and indicated that this
most likely arose from changes in water structure produced by the
presence of high concentrations of salts (this was also suggested
by overtone bands attributed to water molecule aggregates {cf.,
Kleeberg 1987; the ability of salt to influence the H-bonding in
water is only seen in the immediate environment of the ions (Omta
et al. 2003 Science 301, 347-34) which explains why high salt
concentrations are needed affect the overall water structure and
promote Hofmeister activities}. Grant D et al 1987 Biochem J. 244,
143-149 (Abbreviated list of multi-elements in heparin; the single
ion form of heparin should also have been reported to have a list
of these elements, albeit present in a much lesser amounts) Cf CPS
2000 Chemistry Preprint Archive , 2000 Oct, 94-104 available at
http://preprint.chemweb.com/biochem.001002Multi element content of
heparin (permanent internet file) The sample of sodium heparin
chosen for evaluation by SSMS had been donated by a major
pharmaceutical company presumably because of it was considered to
be highly suitable for conducting academic biochemical researches.
A highly purified sample using a standard industrial single salt
heparin preparatory procedure was also studied by SSMS evaluation.
Both heparins were found to have SSMS profiles similar to other
natural polyanions (i.e. alginate or fulvate-like) multi-element
matrices. These multi-element contents correlated (in log-log plots
similar to those shown by Haraguchi, 2004) with those of human
blood serum, human hair, marine alginates, seawater and the natural
fulvates from geological deposits. A considerably body of
literature was later found which supported the notion that
commercial heparins are always contaminated to varying extents by
such elements as Si ,Al, Cu, Zn, Mn, As, V, Ca, Sr and Ba. Cf.
Harrison GE Sutton A Nature 1963 (4869) 809; Bowen HJM in Trace
Element in Biochemistry, Academic Press, London, 1966; Heineman G
Vogt W Biol Trace Elem Res. 2000, 75, 227-234; Alcock NM Serum
versus plasma for trace metal analysis Elem Metab Man Ani Proc Int
Symp 4th 1981 (Pub 1982) Eds JM Gawthorme, JMMMC Howell CL White p
678-680, Springer Verlag Berlin; Schwarz KA PNAS USA 1973. 70,
1608-1612; Bohrer D et al J Parenteral Enteral Nutrition 2005, 29
Bohrer D et al RBA 2004 36 (2) 99-103. The original report of these
SSMS data was made by Moffat CF Ph D Thesis Synthesis,
Characterizsation and Applications of Chemically Modified Heparins
University of Aberdeen 1987 p 187-18 Grant D Tait MI Long WF
Williamson FB Microstructure-dependent crystallization modulation
by alginates (unpublished) Grant D Somers JA Tait MI Long WF
Williamson FB Anti-calcite crystallisation activities of
carrageenans Posters presented by MI Tait at the XIIIth
International Seaweed Symposium Vancouver 13-18 August, 1989 Grant
D et al (heparin-polypeptide interaction involvement of
polymer-associated water) Biochem J 1991 277, 569-571 Grant D 2000
web.ukonline.co.uk/dgrant/dg Grant D et al (dependence on
counter-ion of the degree of hydration of heparin) Biochem Soc
Trans 1990, 18, 1293-1294 Haraguch H 2004 J Anal At Spectrom. 19,
5-14 Israelachvile J 1987 PNAS USA 84 4722-4724 Kleeberg H 1987
Proc Symposium in Honor of WAP Luck Marburg FRG
Kreuger J et al 2005 J Biol Chem 389, 145-150 [the
oligosaccharides studied had the same charge densities, this seemed
to suggest that charge density was the important factor for target
protein binding not the way the charges were disposed along the
oligosaccharides] Lyon M Gallagher JT Matrix Biol 1998, 17, 485-493
Cf Esko JD Lindahl U. Suggested reading list entitled Molecular
diversity of heparan sulfate available at
http://www.jci.org/content/full/108/2/169/DC1 Muelli H et al. 1999
Biophys J 76 (2) 1072-1079 Nader HB Medeiros MGL Paiva JF Paiva VMP
Jeronimo SMB Ferreira TMPC Dietrich CP (1983) Comp Biochem Physiol.
76, 433-436 (Relationship between habitat salinity and the average
total sulphated glycsoaminoglycan contents in fifteen species of
Crustacea, Pelecypoda and Gastropoda) Park PW et al 2000 J Biol
Chem 275 29923-29926 Purdey M (2004) Barium and multiple sclerosis
(heparan sulphate mechanism) Sasisekharan R Shriver Z Venkataraman
G Narayanasanu U Nat Rev Cancer 2002 2(7) 521-528 Wassermann A
(1949) Cation adsorption by brown algae. The mode of occurrence of
alginic acid Annals of Botany N.S. XIII (49) 79-88 Cf Black WAP
Mitchell RL (1952) Trace elements in the common algae and in sea
water J Mar Biol Asoc UK 30 (3) 575-584 (Alginates also bind to
inorganic surfaces in a highly microstructure-discriminated manner
(1); this seems also to be the case for animal polysaccharides and
such binding could conceivable by utilized for sequence evaluation
purposes).
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MANUSCRIPTS Preliminary Notes DEALING WITH THE ENTHALPY-ENTROPY
COMPENSATION EFFECT Ms. 0Consideration Of How Constancy Of A
Sub-Transition State Free Energy Flow Process Arising From
Channeling of Energy May Generate Exact Enthalpy Entropy
Compensation so that in a set of rate constants for chemically
related processes
kr (where lnkr=AexpEa/RT) Ea becomes a linear function of logA]
If chemical reactions proceed via the formation of transition state
complexes in which the driving force for the reaction is provided
by the (Gibbs-Helmholtz) Free Energy (F)
F = H-TS[H (enthalpy) T (absolute Temperature) x S
(entropy)]
(1)
and if this driving force is exerted only at the actual part of
the transition state complex which becomes changed* then for any
set of chemical reactions (in which e.g. for a wide range of
starting molecules which all contain the same (or a similar)
sub-structure on which chemical transformation is performed) the
consequence of this restriction to control the actual reacting
centre by a related process over the whole set of reaction rate
determining processes for which the values of
Fare (approximately) constant,then comparison (of F, H or S)
between members of a set of such selected chemicalreactions must
show that such values of
F are (approximately) zero,viz.substituting equation (2) in
equation (1) gives
F 0
(2) ; H TS (3)
i.e. an (approximate) enthalpy ( H)-entropy ( S) compensation
then exists for appropriate sets of rate constantsThis simple
argument shows how the poorly understood enthalpy-entropy
compensation process may arise simply from a conventional free
energy driving mechanism which acts only upon a restricted reaction
channel in the transition state complex.
In equation (2) T (=, the Leffler isothermal temperature at
which all reactions in the selected set proceed at equal
rate).(*This differs from the model of the transition state complex
which was proposed by some later variations of the transition state
theory which suggested that coupling of vibrations from distant
parts of this molecule could contribute to energy flow) The above
argument uses a single value of free energy, F , i.e. only one part
of the conventional free energy driving force, ie. not, (as
convention dictates) the change in free energy F which is
associated with the completed reaction ; this use of partial time
invariant free energy per se and not its variation time over the
process of chemical change indicates that the role of time as a
processor of free energy is being changed from that conceived in
the clasical thermodynamics-derived expression of chemical
affinity.
Ms 0-1
The Isokinetic Temperature Phenomenon May Give Rise To A
General-Throughout-Chemistry Stochastic Structural Reorganization
Phenomena.It should be noted that enthalpy-entropy compensation/
isokinetic temperature occurs widely throughout chemistry (and also
throughout physics) and similarly random structural reorganization
of chemical substances arise under controlled pyrolysis conditions.
These two sets of phenomena are now putatively directly linked
together.
Stochastic Structural Reorganization The process by which during
heating above a critical temperature, all types of chemical
substances throughout the periodic table can under their
individally appropriately (pyrolysis) temperature conditions
undergo complex structural reorganizations which lead to the
formation of apparently highly complex mixtures of final products.
While pyrolysis of non-carbon (inorganic) systems tend to occur at
lower temperature that do those for carbon centered (organic)
structures a similar underlying randomization of side chains about
a core structure mechanism may determine the outcomes of both kinds
of pyrolysis processes (conducted e.g. under sealed tube
conditions). Examples include the various poly inorganic oxy acid
esters (e.g. the polysilicic acid esters and the polyphosphoric
acid esters for which the process of P-O-P bond formation and
redistribution in the set of [P(O)(OR)3 (P)-O-P(O)(OR)2
{(P)-O-}2P(O)(OR) {(P)-O-}3P(O) give rise to ortho, (monomer) and
condensed phosphates of linear chain, crosslinked (branched) chain
and ring structures via the ring/chain ratio plus the operation of
the sets of reactions: monomer + middles = 2 ends; end + branch = 2
middles]. The above behavior putatively arise simply because of the
occurrence of a general enthalpy-entropy compensation behavior
facilitated by the exitence of a critical temperature. (In sets of
chemcial reactions which exhibit enthalpy-entropy compensation
there exists an isokinetic temperature at which all rates within
these sets of such reactions becomes equal and the products of
these sets of compensated reaction processes (especially if they
are conducted in a system which leads to polymeric structures) tend
to show very clearly identifiable stochastic outcomes (or for a
range of progressively near isokinetic conditions a range of
progressively near-stochastic outcomes arise).
MSS02
Chemical Affinity, The Driving Force of Chemical Reactivity
Re-Defined for Stochastic Chemical Reactivity It should be noted
that historically the original idea proposed by Bertholet and
Thomsen in the early nineteenth century was that the heat produced
during a reaction was a useful indicator of chemical affinity or
the driving force behind chemical reactions. This could not,
however, explain why endothermic reactions can occur spontaneously.
Hence it was suggested (by Gibbs VantHoff and Le Chatelier) that
the proper definition of the chemical reactivity (athe driving
force or chemical affinity) is the maximum work which a chemical
reaction can perform. Hence the Gibbs-Helmholz concept of free
energy F=H-TS Work & Free Energy The classical concept of
chemical reactivity, the Gibbs-Helmholtz free energy F (=H-TS)
change in F as a driving force was ultimately derived from the
hypothesis that reactions could occur spontaneously only if such
reactions could be made to perform useful work. However, the
stochastic reorganization (scrambling) reactions which came to
light only after such modern analytical techniques as NMR were
introduced in the twentieth century, seemed to indicate that
chemical structure alteration could also arise spontaneously under
conditions where the overall free energy in the reaction vessel
does not change, and therefore the idea that the magnitude of
potential free energy change is what always primarily causes
chemical transformations to occur (and always thereby potentially
performs work) seems to be flawed. What then can give a more
universally valid index of chemical reactivity? (It should be n
oted that the general occurrence of certain extrathermodynamic free
energy relationships which were not predictable from classical
thermodynamics also questions the original ideas relating to how
the overall free energy change equates to chemical reactivity).
Stochastic (reversible reaction quasi-equilibria) chemical
reactivity during which in the overall stoichiometric process, free
energy is conserved perhaps should be distinguished from the type
of nonstochastic chemical reactivity where free energy change
remains a valid concept as a driving force for chemical reactivity.
It now seems worthwhile instead, for the elucidation of the nature
stochastic processes to re-focus more on the isokinetic temperature
to consider how this relates to stochastic chemical reactivity
(which is putatively a central consequence of the existence of
enthalpy-entropy compensation) which putatively dictates the
outcome of the (free-energy change-free) stochastic processes.
This draws attention to temperature per se and the isokinetic
temperature (T) in particular as a possible usely focus for
deriving a more general driving force for chemical transformation.
MSS03The Fluctuation Theorem
suggests why F (and not F) may be a useful measure for the
chemical reactivity driving force in compensated chemical
systems.It should be noted that S and not S appears in the Evans
equation which may be written S = P/t
(where P = expSt; antilog P = P= St where t is time and P is the
ratio of the probabilities that S will take a positive or a
negative value (i.e. that the direction of time will be positive or
negative)) Substituting Evans S in F =H-TS, F = H-TP/t From the
Leffler equation (H=ST, T = H/S (where T is the isokinetic
temperature))
when TTF H-[H/S]P/t If H1 chloride dehydrochlorination and
(similarly also to C=C isomerisations of Clcontaining olefins).
Actual rate determining (perhaps heterogeneous) transition state
complexes all lead to the (future) formation of >C=C< from
HC-Cl (this includes chlorinated alipahtic molecule
dehydrochlorination as well as chlorinated aliphatic substance
isomerisation) in which the set of log A values are not restricted
[as required by simple application of classical
thermodynamics-based theories to a value of ca. 13.5] but vary over
a wide range of values e.g. 2-20 (for kr sec-1 (apparent
unimolecular rate processes) and even if the actual value is
influenced by the surface polyion catalyst assisted processing) the
(overall) value of Ea for any particular starting substance in the
set is determined solely by the value of log A (which requires to
obey the Leffler isokinetic relationship logA = Ea, [where is the
isothermal temperature at which all reactions in the set occur at
the same rate]). Reverse Time Theory The Fluctuation Theorem (Evans
1992, cf. Yang et al. 2002) proposed that for small entities over
small time scales reverse time flow will occur to a varying extent
according to the probability ratio of forward vs.
reverse time = exp. [entropy] . [time]. This time reversal was
proposed to be exponentially size-related so that only forward time
need be considered for larger particles such as the machines for
which classical thermodynamics was designed, but for small-sized,
short lifetime entities such as typical chemical molecules and
transition state complexes these are now predicted to experience a
real reverse time processing. This may be a critical requirement
for all chemical reactivity. It is also then the ultimate origin of
the enthalpy-entropy compensation phenomenon observed in sets of
(chemical logic future state probability) rate constants. For
individual series of chemical reactions (irrespective of the
reaction mechanism) the products of such reactions can be
considered to feedback virtual information (as it were from the
future) into the series of their transition states so that the
precise rate by which these products can be generated is achieved
by a balance between the overall observed logA and Ea values. These
entropy and enthalpy changes are then not independent variables but
are determined by how matter interacts with virtual time in the
virtual space of the transition state complex where the effect of
temperature on a virtual conjoined chemical potential [the
enthalpy-entropy] is determined by such a compensation process.
This redefines what chemical reactivity actually is.
______________________________________________
______________________________________________
_____________________________________________
Other ManuscriptsDG Note 27/4/12
15. Van Wazer Structural Reorganization
A review (which was originally drafted in 1975) of ideas
generated from my participation in J.R. Van Wazers Structural-
Reorganization-Throughout-The-Periodic-Table research program
(which had been offered but not published or otherwise put to use)
is now re-formatted below.
---------------------------------------------------------------------------------------SCRAMBLING
REACTIONS David Grant, B.Sc., Ph.D. During the latter part of the
eighteenth century, Berthollet and Proust debated the constancy of
the combining proportions of elements in chemical species, (1).
Berthollet recognized the importance of equilibria, regarding
constant proportions as being the exception. There is a grain of
truth in this, e.g., polymeric and amorphous species can exhibit
variable compositions, and, while numerous compounds including
those based on carbon backbones have a high probability of
remaining unchanged for a long time, some substances having central
atoms other than carbon at structural centers are intrinsically of
lower stability than are purely organic molecular species. This
applies to the liquid phase which can facilitate rapid molecular
rearrangements to occur (and most especially if this process is
fast with respect to the time required to separate the individual
molecular species then the scrambled product is what is most
commonly encountered). This scrambling, may, however, not be
detected by vibrational spectroscopy or by X-ray diffraction.
Numerous reaction products, previously though to be single
compounds have been found to be the scrambled mixtures which, if at
equilibrium will exhibit some reproducible physical properties in a
manner similar to that of pure compounds. The most general form of
scrambling was established by Van Wazer, (2) (ca. 1955) who
extended the earlier concepts of Flory, and demonstrated that
equilibria of which the following is typical, are
established:(RO)2>P(O)(OR) (neso) + -O-P(O)(OR)-O- (middles) 2
O-P(O)Ge< (4 co-ord.) (11), >Sn< (4 co-ord.) (12),
>Si< (4 co-ord.) (13), -B< (3 co-ord.) (14), [and also,
e.g., RnMX4-n (R = alkyl etc., X = halogen, M = Ge, Sn, Si, etc.)].
Recent interest has been shown in CO exchange in cluster compounds,
(15); different sites may exhibit markedly different exchange
rates. Cf., Fe3 (CO)12 scrambling (15a). Examples of scrambling in
polymer systems are: in polysiloxanes, (16); -silicates, (17);
-sulphates, (18); -sulphones, (19); -sulphides, (20); -selenides,
(20); -borates, (21); -phosphates, (22); -phosphonates, (23);
-ethane, oxy,diphosphonates, (24); -arsenites, (25);
-germthioxanes, (26); -(fluoro)arsenious methylimides, (27) and
-tin sulphides, (28). Scrambling (at ambient temperature), of
alkoxyl vs. Cl groups on -V(O)< is some 107 time faster than on
-P(O)< but both systems are similarly random, (19). An example
of scrambling on V(O)< (V(O)Cl3 / (CH3)3Si-O-Si(CH3)3) is shown
in Fig. 1
Fig.1
[R=2Si/(V+2Si)]
The greater rates of scrambling on transition-metal centers may
give rise to fluxional activity (rapid, often intramolecular
NMR-detected scrambling) (29). The use of transition-metal
compounds as catalysts for organic reactions, e.g., in
hydrogenation, isomerization and polymerization, seems to be
afforded by the scrambling potential at the metal, e.g.,
scrambling-related polymer generation arises from the -olefin
monomer additions to the metalcentered scrambling centers which are
the active sites of the Ziegler-Natta polymerization catalysts.
In
the polymer chain propagation process the transition-metal forms
metal-carbon bonds into which bonded olefinic bonds insert. This is
likely to be a reversible (equilibrium) reaction, but is far
displaced towards the polymer form at a polymerization temperature
of ca. 70oC (30). Whether isotactic or stereospecific polymers
arise during this insertion process seems to be dependent on the
rate of structural reorganization of metal bound co-ligands. A
further example of organic reaction catalysis at metal centers is
the metathesis of olefins at W and Mo centers, which leads to an
apparent scrambling of the alkyl groups about the double bond,
(31). Scrambling may be catalyzed both positively or negatively,
e.g., phosphorus halides scrambling is accelerated by H2O (32); for
boron halides, scrambling is inhibited by bases, (33). There is
probably no single type of mechanism which can explain scrambling
reactions. Under scrambling conditions a mechanistic approach to
the rationalization of chemical reaction products obtained at
sub-scrambling temperature, so useful for organic reactions at
near-ambient temperatures, is much less helpful for achieving an
understanding of scrambling process. The important criteria are now
knowledge of the equilibria (perhaps more accurately described as
[enthalpy-entropy compensated] extrathermodynamic pseudoequilibria)
which govern this behavior, (34). A general (first order
approximation) principle of scrambling is that the type of
equilibrium (e.g. random or non-random) is dependent on the ligands
and is independent of the sites; the rate of scrambling, however,
depends on the site, (35). Carbon is the slowest site. Scrambling
of hydrocarbons (e.g. at 1000oC) gives CH4, C2H6, C3H8 and char
(closed system). Phosphorus hydrides behave similarly (char now
being red phosphorus), as do silicon hydrides, (36). The outcome of
high temperature scrambling behavior of hydrocarbons is derivable
from the accurate thermodynamic data which is available for these
compounds, and the above scrambled corresponds to a thermodynamic
equilibrium. However, at lower temperatures, reversible exchange
between aliphatic and aromatic carbon-based systems, occurs. These
are likely to be pseudo-equilibria, where the forward and reverse
rates are not quite equal, and proceed by different mechanisms;
this situation is illustrated by the scrambling of chlorocarbons in
sealed-tubes, where all chlorocarbons which have been studied give
CCl4, C2Cl6 and C6Cl6, with inappreciable char formation, (37). The
phenomenon of aromaticity may be considered to be a double bond
scrambling around the ring. Negative catalysis (Fe(CO)3 complexing
sites) slow the process sufficiently for individual
cyclohexatrienes to be distinguished, (38). In boranes and related
compounds, a variety of BHB scrambling reactions have been reported
, e.g. with B3H8 , (39),
Silicates scramble near-randomly, (17), therefore giving rise to
appreciable amounts of a large number of structures. Nucleation of
crystallization of a particular structure can remove it form the
equilibrium, eventually converting all of the molecules present.
[Bond exchange also can lead to flow in compositions beyond the gel
point. In inorganic polymers such as silicates bond exchange can
lead to flow whereas flow in organic polymers flow most often
involves the sliding of the intact molecules over each other].
The formation of quite complicated structures in high yield in
pre-biotic conditions could have been an outcome of scrambling
reactions and subsequent nucleation of specific sub-types of
molecules allowing the formation of specific proteinoid and
poly-sugar-triphosphate molecules to be achieved in high yield.
References (1) -Cf. A Short History of Chemistry , J.R.
Partington, Macmilllan, London, 1957, p. 153 (2) Phosphorus and Its
Compounds Vol I, J.R. Van Wazer, Interscience, New York, 1959; C.F.
Callis , J. R Van Wazer, J.N. Schoolery and W.A. Anderson, J Amer.
Chem. Soc., (1957),79, 2719; J.R. Van Wazer, C.F. Callis and J.N.
Schoolery, (1955), 77, 4945 (3) E. Schwarzman and J.R. Van Wazer,
J. Amer. Chem. Soc., (1960), 82, 6009 (3a) cf., e.g., J.R. Van
Wazer, Amer. Scientist, ref. (36) (4) G. Caligingaert and H.A.
Beatty, J. Amer. Chem. Soc. (1939), 61, 2748 G. Calingaert, H.A.
Beatty and H.R. Neal, ibid., (1939), 61, 2755 G. Calingaert and H
Soros, ibid., (1939), 61, 2758 G. Calingaert, H.A. Beatty and H.
Soroos, ibid. (1940), 62, 1099 (5) P.J. Flory, J. Amer Chem. Soc.,
(1942), 64, 2205 (6) G.S. Forbes and H.H. Anderson, J. Amer. Chem.
Soc., (1944), 66, 931 (7) R.J.H. Clark and P.D. Mitchell, J.Chem.
Soc. Dalton, 1972, 2429 (8) L.C.D. Groenwege and J.H. Payne Jr., J.
Amer Chem. Soc., (1959), 81, 6357 (9) P.A.W. Dean and D.F. Evans,
J. Chem. Soc., A, 1970, 2569
(10) M. D. Rausch and J.R. Van Wazer. Inorg. Chem. (1964), 3,761
Cf. J.C. Lockart, Chem. Rev., (1965), 65, 131 (11) G.M. Burch and
J.R.Van Wazer, J. Chem. Soc. A. 1966, 586 cf. Inorg. Chem., 1964,
3, 268 (12) J.J. Burke and P.C. Lauterbur, J. Amer. Chem. Soc.
(1961), 83, 326; G.S. Forbes and H.H. Anderson, ibid., (1945), 67,
1911; (1944), 66, 931, G. Calingaert, H. Soroos and V. Hnizda,
ibid., (1940), 62, 1107 D. Grant and J.R. Van Wazer, J.
Organometal. Chem., (1965), 4, 229 (13) K. Moedritzer and J.R. Van
Wazer Inorg. Chem. (1964), 3, 268 and refs. cited; cf J.R. Van
Wazer and K. Moedritzer, J. Inorg. Nucl. Chem. (1964), 24, 73 (14)
H.K Hofmeister and J.R. Van Wazer, J Inorg. Nucl. Chem., (1964),
26, 1209 M.F. Lappert, M.R. Litzow et al., J. Chem Soc.(A) 1971,
383; (15) L. Milone, S. Aime, E.W. Randall and E Rosenberg J.C.S.
Chem. Commun., 1975, 452 T.J. Marks and G.W. Grynkewich, J.
Organometallic Chem., (1975), 91, C9-12,
F.A. Cotton, D.L. Hunter and P. Lahuerti, Inorg. Chem., (1975),
14, 511. (15a) B.F.G. Johnson, J.C.S. Chem. Commun., 1976, 703 (16)
K. Moedritzer and J. R. Van Wazer, J. Amer. Chem. Soc. (1964), 86,
802 (17) D. Grant, J. Inorg. Nucl. Chem., (1967), 29, 69 R.O.
Gould, B.M. Lowe and N.A. MacGilp, J.C.S. Chem. Commun., 1974, 720
(18) J.R. Van Wazer, D. Grant and C.H. Dungan, J. Amer. Chem. Soc.,
(1965), 87, 3333 (19) Unpublished work of D. Grant and J.R. Van
Wazer (20) J.R. Van Wazer, D. Grant, J. Amer. Chem. Soc., (1964),
86, 3012 (21) H.K. Hofmeister and J.R. Van Wazer, J Inorg. Nucl.
Chem., (1964), 26, 1201 (22) J.R. Van Wazer, C.F. Callis, J.N.
Shoolery and R.C. Jones, J. A Amer. Chem. Soc., (1956), 78, 5709
and 5715 C.F. Callis, J.R. Van Wazer, J.N. Shoolery and W.A.
Anderson, J. Amer. Chem. Soc. (1957), 79, 2719 D.P. Ames, S.
Ohashi, C.F. Callis and J.R. Van Wazer ibid., (1959), 81, 6350 M.
M. Crutchfield, C.F. Callis, R.R. Irani and G.C. Roth, Inorg.
Chem., (1962), 1, 813 L.C.D. Groenweghe, J.H. Payne and J.R. Van
Wazer, J. Amer. Chem. Soc., (1960), 82, 5305 E. Schwarzmann and
J.R. Van Wazer, ibid., (1961), 83, 365 D.R. Cooper and J.A.
Semlyen, Polymer, (1972), 13, 414 J.R. Van Wazer and S. Norval, J.
Amer. Chem. Soc., (1966), 88, 4415 L.C.D. Groenweghe and J.H. Payne
Jr., J. Amer. Chem. Soc., (1959), 81, 6357 (23) D. Grant, J.R. Van
Wazer and C.H. Dungan , J. Polymer Sci., (1967),A-1,5, 57 (24)
Unpublished work of D. Grant (Glasgow University manuscript in
preparation [(added later: eventually published in Eur. Polym. J.
(1979), 15, 1161)] (25) J.R. Van Wazer, K. Moedritzer and D.W.
Matula, J. Amer. Chem. Soc., (1964), 86, 807 (26) K. Moedritzer and
J.R. Van Wazer, J. Amer. Chem. Soc., (1968), 90, 1520 (27) M.D.
Rausch, J.R. Van Wazer and K. Moedritzer, J. Amer. Chem. Soc.,
(1964), 86, 814 (28) K. Moedritzer and J.R. Van Wazer, Inorg.
Chem., (1964), 3, 943 (29) F.A. Cotton, Chem. Brit., (1968), 4, 345
Cf. S. Cradock, E.A.V. Ebsworth, H. Moretto and D.W.H. Rankin,
J.C.S. Dalton, 1975, 390; A.J. Campbell, C.A. Fyfe and E. Maslowsky
Jr., Chem Commun., 1971, 1032; P.C. Angus and
S.R. Stobart, J.C.S. Dalton, 1973, 2374 (30) Cf. D. Grant , J
Polymer Sci., Polymer Letters , (1975), 13,1 (31) Cf. N. Calderon
and R.N. Hinrichs, Chemtech., (1974), 4, 627 E.L. Muetterties and
M.A. Busch, J.C.S. Chem. Commun., 1974, 754 and refs. cited; A.J.
Amass, Br. Polymer J. (1972), 4, 327
(32) A.D. Jordan and R.G. Cavell, Inorg. Chem., (1972), 11, 564
(33) B. Benton-Jones, M.E.A. Davidson, J.S. Hartman, J.J. Klassen
and J.M. Miller, J.C.S. Dalton, 1972, 2603 Cf. M.J. Bula, J.S.
Hartman and C.V. Raman, ibid., 1974, 725 (34) D.W. Matula, L.C.D.
Groenweghe and J.R. Van Wazer, J Chem. Phys. (1964), 41, 3105 R.M.
Levy and J.R. Van Wazer, ibid., (1966), 45, 1824 L.C.D. Groenweghe,
J.R. Van Wazer and A.W. Dickenson, Anal. Chem., (1964), 36, 303
J.R. Van Wazer and K. Moedritzer, Angew. Chem. Internat. Edit.,
(1966), 5, 341 K. Moedritzer, Inorg. Chim. Acta, 1970, 4, 613 J.R.
Van Wazer and L.C.D. Groenweghe, Nuclear Magnetic Resonance in
Chemistry, B. Pesce, Ed., (1965), 283 J.R. Van Wazer Inorganic
Polymer Chemistry J. Macromol. Sci., 1967, A1, 29 J.C. Lockart,
Chem. Rev., (1965), 65, 131Note added to ms. later: the Van Wazer
scrambling phenomena are likely to be afforded by
extrathermodynamic pseudoequilibria associated with
enthalpy-entropy compensation phenomena, the general occurrence of
which throughout biology, chemistry and physics putatively requires
a re-think of classical thermodynamics, an e.g. involves
application of reverse time and vacuum energy concepts ]
(35) J.R. Van Wazer, Proc. Conf. Coord. Chem., 8th, Vienna,
1964, Springer-Verlag, Vienna, Ed. V. Gutman, p.162 (36) J.R. Van
Wazer, Amer. Scientist, (1962) , 50, 450 (37) N.E. Aubrey and J.R.
Van Wazer, J. Amer Chem Soc., (1964), 86, 4380 D. Grant, J. Appl.
Chem. Biotechnol., (1974), 24, 49 (38) R. Victor, R. Ben-Shoshan
and S. Sarel, Chem. Commun., 1970, 1680 (39) H. Beall and C.H.
Bushweller, Chem. Rev., (1973), 73, 465 cf, E.L. Muetterties, E.L.
Hoel, C.G. Salentine and M.F. Hawthorne, Inorg. Chem., (1975), 14,
950 Further References, Scrambling Centre Indicated. J.R. Van Wazer
et al, J. Inorg. Nucl. Chem. (1964), 26, 1209 (boron); Inorg.
Chem., (1964), 3, 139 (arsenic); J. Amer. Chem. Soc., (1964), 86,
811; Inorg. Chem., (1964), 3, 280 (phosphorus); Ibid., (1965), 4,
1294 (silicon) (silicon, germanium) J. Inorg. Nucl. Chem., (1964),
26, 737 (silicon) J. Organometal. Chem., (1968), 12, 69
(silicon)
Ibid., (1975), 85, 41 ([silicon] phosphorus) Inorg. Chim. Acta.
(1967), 1, 407; Ibid., (1967), 1, (1967), 152 (silicon, germanium)
(cf. K. Moedritzer ibid. (1971), 5, 547; (1974), 10, 163 (silicon,
germanium K.M. Abraham and J.R. Van Wazer, J. Inorg. Nucl. Chem.,
(1975), 37, 541 (silicon, germanium) E. Fluck, J.R. Van Wazer and
L.C.D. Groenweghe, J. Amer. Chem. Soc., (1959), 81, 6363
(phosphorus) J. Inorg. Nucl. Chem., (1967), 29,1571 (germanium);
Ibid. (1964), 26, 737; Ibid., (1967), 29, 1851 (silicon) Inorg.
Chem., (1965), 4, 1294 (review) J. Chem. Phys. (1964), 41, 3122
(several elements) J.G. Reiss and S.C. Pace, Inorg. Chim. Acta,
(1974), 9, 61 (silicon) M.W. Grant and R.H. Prince, J. Chem. Soc.,
(A), 1969, 1138 (silicon)(germanium) F. Glocking, S.R. Stobart and
J.J. Sweeney, J.C.S. Dalton, 1973, 2029 (mercury); A.G. Lee and
G.M. Sheldrick, ibid., (A), 1969, 1055 (thallium); J.A.S. Howell
and K.C. Moss, ibid., (A), 1971, 2483 (tantalum); R. Davis, M.N.S.
Hill, C.E. Holloway, B.F.G. Johnson and K.H. Al-Obaidi, ibid., (A),
1971, 994 (molybdenum and tungsten); H. Hagnauer, G.C. Stocco and
R.S. Tobias, J. Organometal. Chem., (1972), 46, 179 (gold); C.E.
Holloway, J. Coord. Chem., 1971,1, 253 (tantalum); J. Evans, B.F.G.
Johnson, J. Lewis and J.R. Norton, J.C.S. Chem, Commun., 1973, 807
(rhodium); J.F. Nixon, B. Wilkins and D.A. Clement, J.C.S. Dalton,
1974, 1993 (rhodium); J. Evans, B.F.G. Johnson, J. Lewis and
R.Watt, ibid., 1974, 2368 (rhodium); M. Green and G.J. Parker,
ibid., 1974, 333 (rhodium and iridium); A.J.P. Domingos, B.F.G.
Johnson and J. Lewis, ibid., 1974, 145 (ruthenium); T.H. Whitesides
and R.A. Budnik, J.C.S. Chem. Commun., 1974, 302 (ruthenium); F.
Calderazzo, M. Pasquali and T. Salvatori, J.C.S. Dalton, 1974, 1102
(uranium); R.J. Cross and N.H. Tennent, ibid., 1974, 1444
(platinium); T. Mole, Organometal. Reactions, (1970),1,1, (review,
aluminum); N.S. Ham and T. Mole, Progr. Nuclear Magnetic Resonance
Spectrosocpy, Ed. J.W. Feeney and L.H. Sutcliff, Pergamon Press,
London, (1969), 4, 91 (review); F.A. Cotton, Accounts Chem. Res.,
(1968), 1, 251 (review). (Examples of scrambling on carbon); K.
Moedritzer and J.R. Van Wazer, J. Org. Chem., (1965), 30, 3920
(polyoxymethylenes); Ibid., (1965), 30, 3925 (acetals and
orthoformates) J.T. Bursey , M.M. Bursey and D.G.I. Kingston, Chem.
Rev., (1973), 73, 191 (intramolecular hydrogen transfer on carbon
during mass spectrometery).Added Later Following my postgraduate
research (which had been funded by an Albright & Wilson Mfg.
U.K. Studentship and supervised by D.S. Payne at the University of
Glasgow, Scotland, U.K, (earning Ph.D. in 1962 for a thesis A Study
of Phosphites [cf. D. Grant et al., J. Inorg. Nucl. Chem., 1964,
26, 1985 and ibid., 26, 2103) and a study of the use of Ce(IV) for
oxidative analytical chemistry [Anal. Chim. Acta, 1961, 25, 422 ]),
I had the honor to work as a Postdoctoral Fellow with John R Van
Wazer in his (Monsanto Co, St Louis) research group (which
conducted fundamental researches into the phenomenon of stochastic
structural reorganization; this processes, which had been found to
determine the chemical constitution of condensed phosphates (and
further seemed to offer insight into the in biological use of
condensed phosphates for energy transfer and as a basic determinant
of the structure and activity of nucleic
acids), also seemed to allow for a fuller understanding of the
thermal stability of numerous kinds of substances (including
inorganic, organometallic and organic polymers). I later
contributed to I.S.R. U.K. research activities (which ceased in
1975) [cf., e.g. E.W. Duck et al. Eur. Polymer J., 1974, 10, 77;
ibid., 481; ibid., 1979, 15, 625) and, The Pertinence Of The
Scrambling Behaviour of Ligands on Transition-Metal Centres to
Ziegler-Natta Catalyst Activities (J. Polymer Sci., Polymer Lett.,
1975, 13, 1 ) which suggested that the polymerization of olefins
(as well as the related process of olefin metathesis) occurred by a
process akin to Van Wazer structural reorganization at the
catalytic center monomer adducts].
Mss. ex University of Aberdeen
Archival Literature Surveys from personal files retained from
Marischal College Polysaccharide Research GroupD. Grant, Ph.D.,
Turriff AB53, Scotland, UK
Contents
A Survey Conducted by Nancy EWoodhead
B Survey Conducted by David GrantA A Perspective Suggested by
Peer-Reviewed Literature a of How Glycosaminoglycans May Mediate
Cellular Activities Including Proliferation and Transformation
----------------------------------
A topic which is believed to be of public interest was the
subject of a presentation made in 1982 (to the W.F. Long, F.B.
Williamson Polysaccharide Research Group at Marischal College
Aberdeen) by Nancy E. Woodhead. This document contains an edited
transcript of my shorthand notes made at the time to which I now
append an update of the peer-reviewed literature in this field and
also an edited version of a hypothesis
(Ascorbate and Nitric Oxide in Redox Control of Heparan
Sulphate) which has originally posted on the internet in 2000 on a
site which is no longer active.
=====================================================================
Glycosaminoglycans and Cellular Transformation Prior to 1982
literature reports in this field were classified by Nancy Woodhead
as follows: 1. 2. 3. 4. 5. Experiments directly relating
glycosaminoglycans (GAGs) to cell growth control and
Transformation. Alterations in GAG contents of cultured cells after
transformation. Alterations of GAG contents of mammalian tumors
compared to normal tissue; [this provides more material than is
available from cells in culture]. Changes in complex composition of
certain cell surface GAGs; [especially of HS)] Searches for a
specific changes in function of cell surface GAGs; [possible
functional change due to regional alterations in GAG
structure].
1. Includes reports of experiments relating GAGs to cell growth
control and cellular transformation; starting from 1932: Year
Author 1932 Zakrezewski 1957 Sister M. Lippman Reported that
heparin suppresses growth of normal embryonic tissue and Jensen
sarcoma tissue. Reported experimental evidence that heparin can act
as a mitotic inhibitor. [This was an in vivo study of the effect of
how administration of subcutaneous heparin affected the measured
size of Ehrlich Ascites tumors in rats. It was shown that heparin,
under the conditions studied, produced a 40-50% regression of
tumors].
1960 Ozzello et al.
Umbilical cord extracted hyaluronate (HA) or chondroitin sulfate
(CS) promoted the growth of human mammary carcinoma cells in
culture. Any of these substance taken singly promoted tumor growth.
Heparin prevented mitosis. Evidence for intracellular action of
heparin. Heparin also caused formation of microvili on cell
surfaces. (Is this an abnormal effect of heparin or is at an
apparent normal intracellular function of heparin-like molecules?)
It was apparent that the phenomenon was probably not a unique
property of EDTA (a high affinity Ca2+ chelator) which had been
known to produce microvilli formation. This outcome may simply be
caused by the removal of Ca2+ from the cell surface. (Heparin-like
molecules may have this function in vivo).
1964 Costachel et al.
1966 Takeuchi
CS enhanced of tumor growth. Hydrocortisone inhibited the growth
of tumors, but this inhibition was prevented by the presence of CS.
Heparin CS and HA : maintained cells in culture after they
degenerated in normal culture medium. Some effect of CS and HA on
cell surfaces was suggested to
1974 Takeuchi et al.
increase their potential for affecting cell growth. 1975 Olin et
al. ? Salt effects ? (and related sources of salt e.g. heparin
etc.) can apparently [link to this document lost] can exert a
concentration-dependent control effect on tumor cell growth. Large
doses inhibited epithelial cell growth but low cell surface doses
accelerated growth. E.g. 50-100g/ml level (at) cell surface
inhibited cell growth while 0.5g/ml promoted growth. Summary of the
pre-1975 findings 1. Polyanions can enhance tumor growth by
protecting cell surface antigenic sites. 2. The production of new
connective tissue giving GAGs is favorable to cancer cell growth
More GAGs (if present) they can be chosen for cancers to (allow
cells to stick?) 3. Effect of heparin on nucleoproteins. Evidence
shows that heparin interacts with proteins in the nucleus (and
thereby affects DNA) and so (affects) protein synthesis. 4. Heparin
removes Ca from cell surfaces. Cellular proliferation might be
affected by this mechanism. Studies which report an Alteration in
GAG content of cultured cells after transformation 1966 Ishimoto et
al. Avian sarcoma virus in chicken embryo fibroblasts led to (i) 5x
increase in HA synthesized, (ii) extracellular HA increases. 1973
Satoh et al. Herpes type II or SV40 virus transforming virus in
hamster embryo fibroblasts led to (i) increased HA (ii) HS
proportion of total GAGs
1977
Hopwood and Dorfman SV40 in human skin fibroblasts led to (i)
increased HA; increased HS, decreased dermatan sulfate (DS). (ii)
HA acid synthesis is inversely proportional to cell density in
normal but not in transformed cells. (i) Primary and permanent cell
lines (Associated) increased CS and increased HS in permanent cell
lines (ii) (Associated) increased DS and increased HS in primary
cell lines. These results were similar for transformed (cell lines)
(these are equivalent to permanent?) Rous sarcoma virus (RSV)
transformed chondrocytes, showed: (i) less cell surface GAGs; (ii)
HS (was) shed into the cell culture medium. (1) Chemical
transformation of liver parenchymal cell clones led to: Increased
CS; production of (usually less) HS.
1978 Dietrich et al.
1979 Mikuni-Takagali and Toole i 1980 Ninomaya et al.
Suggested reason/(consequences) for these changes: (1) CS acts
as stimulant for cell division, with HS and DS having different
roles such as recognition and adhesiveness. (2) HS may act as a
negative control element of growth. (3) Loss of activity of GAG
degrading enzymes or increase in GAG synthesizing enzymes: not a
direct effect of transformation. 1978 Chiarugi et al. Assessed
Mammalian Tumors 100 cases of human cancer studied: normal and
neoplastic GAG content compared: (i) All neoplastic tissue showed
changed GAG contents. (ii) Malignant tissue showed larger changes
than non invasive tumors (iii) Most common effects - increase in CS
or increase in HA or decrease in HA or CS. Often an increase
(occurs in) total GAG
(1) Increase in HA and/or CS is a characteristic abnormality of
GAGs in cancerous tissue. (2) Increase in total GAG in tumor tissue
gives overall change in negative charge associated with the tissue.
------Studies Reporting Changes in Chemical Structure of Cell
Surface GAG Following Cellular Transformation 3TS cell and SV40
transformed cells (i) (ii) 1978 Nakamura et al. HA and CS not
changed. HS from transformed cells elutes at lower ionic strength
from anion exchange column.
1975 Underhill and Keller
AH130 Ascites hepatoma Cell-associated GAG 93% HS
(extracellular) fluid 58% HS, 26% HA, 16% CS Cell associated (i) HS
less sulfated. (ii) HS (is) highly heterogeneous (as indicated by
electrophoresis).
1978 Winterbourne and Mora 3TS/SV3TS cells (i) HS elutes from
anion exchanger at lower anionic strength. 35 3 (ii) S/ H ratio
lower. (But) no change in overall turnover rate of HS. 1979
Chandreschan and Davidson Normal human breast cell line (compared
with) human breast carcinoma cell lines.
Cancer cell lines (i) Mainly CS and HS. (i) Heterogeneous HS.
(ii) Size Charge (and) NAc/N-SO3 altered.
1980 Keller et al.
3TS/SV3T3
(Following transformation) (i) HS charge density is lower. (ii)
8% decrease (occurs) in O-sulfate 1981 Winterbourne and Mora
3TS/SV3TS (i) (ii) (iii) (iv) HS charge-density is lower. O-sulfate
containing disaccharides of HNO2 degraded HS; the same.
O-sulfate-containing oligosaccharides of HNO2 degraded HS show
lower 6-O sulfation. Overall sulfation a decrease occurs in 6
(-O-sulfate).
CONCLUSION(S TO BE) DRAWN FROM THE ABOVE EXPERIMENTS 1. 2. 3. 4.
Change in sulfate incorporation into GAGs may reflect change in
substrate PAPS pool sizes. T antigen* (SV40 early gene product) may
be responsible for change in HS structure. Ca2+ binding of the cell
surface may be altered by lower HS charge. Changes in HS structure
may lead to altered binding to cell surface protein e.g.
fibronectin (this is of interest since fibronectin is not found on
many transformed cells).
* Binds heparin therefore could possibly change the structure of
HS on the cell surface HS was found only on cells expressing T
antigen. -------
Specific Change in Properties of Cell Surface GAGs 1982 Fransson
et al. (i) (ii) (iii) (comparing) 3T3/8V3TS and PyY 3TS cells HS
(is) heterogeneous HS has a lower change density (in transformed
cells) HS iduronate/glucuronate bearing N-sulfate segments (are
less common in transformed cells).
Increased heterogeneity is (also) associated with reduction in
self-aggregation properties. 1982 1983 Culp and Dorfman Highly
N-sulfated HS sequences (bind) most efficiently to fibronectin
affinity columns.
Stamatoglou and Keller 3TS/8V3TS HS elution from fibronectin
(or) collagen. No difference between normal and transformed cells
(when using physiol.) NaCl Only heparin will displace HS from
collagen (but) heparin and DS can displace HS from fibronectin.
1982 Castellot et al.
Smooth muscle cell growth is inhibited by heparin like
substances. Endothelial cells exposed to heparinoids are released
from growth inhibition.
Heparitinase released from cells or platelets may cause
stimulation of mitosis by degrading heparin like compounds. If you
get damage to an endothelial surface to a blood vessel then the
platelets will adhere to this surface (but only if they) release
heparinase and so stimulate cell growth. The release of thrombin
also will occur under these conditions. It should be noted that:
Cancer (n.b. is the) uncontrolled growth of cells. Transformation -
(is the) event leading to cancerous growth of cells. Metastasis (is
the critical-for-cancer-mortality) loss of cells from tumor surface
to form subsidiary tumors elsewhere. N.b. Inflammatory conditions -
(are those conditions where) CS and HS also tend to increase N.b.
also: GAGs structures become altered before or during cellular
transformation. But Validity of Considertion of Fibronectin as a
Driving Force ? Could such evidence point in the wrong direction?
The important events in cellular transformation may be associated
(most specifically) with the GAGs. {Note added later. The current
paradigm is that (usually multiple) mutation(s) of DNA produce
cellular transformation and neoplasia. Whilst this mechanism is
undoubtedly the primary cause of cancer the follow-on effect on the
glycosylation system is putatively also an additional critical part
of the etiologies of these diseases; especially the
transformation-associated alteration of extracellular proteoglycan
glycosylation regulatory functions afforded by HS may actually
cause the greatest damage to the organism by allowing uncontrolled
cellular growth angiogeneiss and metastasis to occur}. N.b. The HS
information encoded processing system is now thought to be a major
epigenetic driver. Chiarugi et al. had noted in 1974 (Biochim
Biophys Acta. 345 283-293) that The effect of N-sulfated polyanions
on tissue growth in vivo and in vitro has been recognized since
1932 (this was intimated by Zakrezewki loc. cit } But (at what
stage) in the transformation process are the HS or other GAGs
related to the change in events involved ? The initial important
change must be there - the insertion of (some) new genetic
interaction. Perhaps a clue can be gained from the circumstances
where Ca is chelated out (cf. thrombin, antithrombin and the
heparin effect) Mammalian GAGs - can be anti-inflammatory -- can be
anti-cancer.
(Cf.) A consideration which might be of relevance is how
cross-linked carrageenan beads can (behave) like proteoglycan
complexes; (they are set in cells but they are not actually in the
cells).
a Adapted from notes made during a lecture/discussion literature
survey of how GAGs (especially heparan sulfate (HS)) participated
in the etiology of cellular transformation and neoplasia presented
to the Marishcal College (Aberdeen) Polysaccharide Research Group*
on 18 November 1982 by Nancy E. Woodhead (then a graduate student
member of the W.F. Long and F.B. Williamson Polysaccharide Research
Group) written down in a University of Aberdeen Lab. Notebook
16/3/82-26/11/82 [Page heading Nancys Talk]
retained by D Grant AB53 UK.
Cf also NE Woodhead et al., IRCS Medical Science : Biochemistry
; Cancer; Cell and Molecular Biology; Connective Tissue, Skin and
Bone ; Pathology [IRCS Med. Sci., 14 427428 (1986) (Heparan
sulfates from fibroblasts exhibiting a temperature-dependent
transformed growth trait). (This was a comparative study of normal
vs. chemicallytransformed cells which exhibited a transformed
growth trait at 37oC. The transformed cells reverted to a normal
growth pattern at a lower temperature. The observed changes in
heparan sulfates may have mediated this phenotype change.These
results remain of topical interest.
*[The hypothesis that cellular proliferation is, at least in
part, determined by the binding of Ca2+ ions to cell surface
glycosaminogycans was, for about thirty years, a principal
researchfocus for a polysaccharide research group headed by W.F.
Long and F.B. Williamson at the University of Aberdeen. Barr L. et
al. reported in 2006 (FASEB J. 20 E963-E975) that a Ca2+ dependent
pathway (involving the completion of the glycosaminogycan protein
linkage tetrasaccharide formation) controls chondroitin and heparan
sulfate proteoglycan biosynthesis].
The Addendum (vide infra) lists a fairly random selection of
more recent similar topic peer-reviewed literature
References Citations given in the 1982 lecture by N.E. Woodhead
are listed below in the order in
which they appear in my notes (which were taken at the time);
these are also listed in the The Heparan Sulphates of Control,
Virally-Transformed and ChemicallyTransformed Fibroblasts Nancy
Elizabeth Woodhead Ph.D. Thesis University of Aberdeen, , 1985. It
should be noted that this thesis also reported for the first time
on how a chemical carcinogen
(N-methyl-N-nitro-N-nitrosoguandine)transformation of cells gave
rise to similar diminution of HS sulphation to that observed with
viral transformation or as is commonly found in HS extracted from
cancer tissue. A previous Aberdeen University Ph.D. Thesis by H.H.K
Watson (1980) had also dealt with related researches.Additional
references to those discussed in the 1982 lecture and which further
support the hypothesis that the etiology of neoplasia could depend
on alteration of GAG composition following cellular transformation
which were Chapter 1.8 [Glycosaminoglycans in Cancer] cited of the
above Thesis are: Kuroda et al. (1974) [Rat tumors] Cancer Res. 34
308-312;
Kupchella et al. (1981) [Rat tumors ] ibid., 41 419-424 Kojima
at al. (1975) Horai et al. (1981) [Human hepatic tumor] ibid.,
502-547 [Human lung tumor] Cancer. 48 2016-2021
Knudsen et al. (1984) [Murine tumors synthesized 20x the amounts
of GAGs in vivo/in vitro] J Cell Biochem. 25 183-196 David and Van
den Berg (1983) [Transformed mouse epithelial cells] J Biol Chem.
258 7338-7344; Eur J Biochem. 1989
178 609-617 Robinson et al. (1984) ibid., 253 668-793 Ohkuboka
(1983) Cancer Res. 43 2712-7 Additional Related-Topic Older
References Mitotic Gelation (Water Structure?) Cf. Chiarugi V.P. et
al. (1974) Biochim Biophys Acta. 345 283-293: Heparin has been
found to prevent mitotic gelation ; (a periodic release of free
heparin occurs in synchrony with the cell cycle); Augusti-Tocco G.
and Chiarugi V.P. (1976) Cell Differentiation 5 (3)161-170 (Surface
glycosaminoglycans as a differentiation cofactor in neuroblastoma
cell culture) the switch from the round to the neuron-like cells
can be obtained by a simple change of the culture conditions, which
causes an increase of cell adhesion this is accompanied by an
increasing ability of cells to retain heparan sulfate. Control of
Cellular Activities by Cell Surface GAG Selective Binding of Ca2+
Cf. Long W.F. and Williamson W.F. loc. cit. and Cf. Vannucchi S. et
al. Biochem J. 1978 170 185-187. Table 4 of this article indicates
that the relative Ca2+ binding capacity of commercial GAGs was
found to be HA 1.00, heparin 2.76, HS 2.00, CS(A) 1.60, CS(B) 1.67
and CS(C) 1.80. Role of Ascorbate as a Heparan Sulfation Control
Agent Watson and Edward (1980) Biochem Soc Trans. 8 134-136 (Cf.
Edward and Oliver (1983) [Ascorbate boosts HS sulfation] ibid., 11
383; ibid. 12 304 {this was confirmed by Kao et al. (1990) Exp Mol
Pathol. 1990 53 1-10}and may be part of the mechanism by which
ascorbate demonstrates anti-cancer activity as indicated, e.g. by
Cameron and Pauling (1985) PNAS 75 4538-4542 cf. ibid., 79
3685-3689})
-------------------------------------------------------------------------------------------------------------------------------------------------Esko
J.D. Rostand K.S. Weinke J.L.(1988) (Tumor formation dependent on
proteoglycan biosynthesis) Science. 241 1092-1096; cf. Barr L. et
al., (2006) 20 E963-E975 (Evidence of calcium-dependent pathways in
the regulation of human 1,3glucuronosyltransferase-1 (GlcAT-I) gene
expression : a key enzyme in proteoglycan synthesis) FASEB J.
[These GAG chains are important regulators in a wide range of
biological events, such as matrix deposition, intracellular
signaling, morphogenesis, cell migration normal and tumor cell
growth] Fedarko N.S. Ishihara M and Conrad H.E. (1989) (Control of
cell division in hepatoma cells by exogenous heparan sulfate
proteoglycan) J Cell Physiol. 139 287-294 PMID 2715188 (Additional
related references accessed by Marion Ross a later member of the
Aberdeen University polysaccharide group)) Zimina N.P. et al.
(1987) Biokhimia. 52 (5) 856-861 [All types of sulfated GAGs in
actively proliferating tissues (except
regenerating tissues) have a reduced degree of sulfation)Kosir
M.A. and Culp L.A. (1988) Surg Forum Med. 39 424-426 Matuoka K et
al. (1984) Cell Structure and Function 9 357-367 [1. HS plays a
particular function in contact regulation of cell proliferation. 3.
Transformation-related changes in the structure of HS molecules do
not much affect the function of HS. 3. The cellular transformation,
however, is accompanied by alteration in the growth regulating
system sensitive to extracellular HS. Heparin inhibited growth in
both normal and transformed cells]
Cf. also Long WF and Williamson FB (1979)
(Glycosaminoglycans, calcium ions and control of cell
proliferation)
IRCS Journal Med Sci. 7 429-434; Cf. also Med Hypoth. 11 285-308
and ibid., 13 385-394 Most of the relevant Aberdeen University
Polysaccharide Research Group publications including those of
N.E. Woodhead (up to 2003) which had been undertaken in part to
advance the above hypothesis were listed by Professor W.F. Long
atweb. abdn.ac.uk/~bch118/publications2003march.doc NE Woodhead et
al. also conducted in vivo and in vitro studies relating to the
Long-Williamson GAG divalent metal ion animal cellular control
hypothesis (cf., Biochem J. 1986 237 281-284)
HS, the ubiquitous component cell surfaces and extracellular
matrices of animals, may affect transformation of cells and also be
a controller of their proliferation, at least in part, via
HS-mediated control of the activities of (Ca2+ and Zn2+) metal ion
signaling activities.Zakrezewki Z. (1933) Z Krebsforsch. 36 513-521
Lippman M. (1957) Cancer Res. 17, 11-14 Ozzello L. et al. (1960)
ibid., 20, 600-605 Costachel O et al. (1964) Exptl Cell Res. 34
542-547 Takeuchi J. (1966) ibid., 26, 797-802 Takeuchi J. et al.
(1976) ibid., 36, 2133-2139 Olin (source not found) Obrink B. et
al. (1975) Conn Tiss Res. 3 187-193 Ishimoto N. et al. (1966) J
Biol Chem. 241 2052-2057 Satoh C. et al. (1973) Proc Natl Acad Sci
USA. 70 54-63 Hopwood J.J. and Dorfman A. (1977) J Biol Chem. 252
4771-4785 Dietrich C.P. and Armelin H.A. (1978) Biochem Biophys Res
Commun. 84 794-801; Cf. Dietrich C.P. and DeOca H .M. ibid., 80
805-812; Mikuni-Takagaki Y. and Toole B.P. (1979) J Biol Chem. 254
8409-8415 Chiarugi V.P. et al. (1978) Cancer Res. 38 4717-4721
Underhill C.B. and Keller J.M. (1975) Biochem Biophys Res Commun.
63 448-454; cf., J Cell Physiol. 89 53-64 Nakamura N. et al. (1978)
Biochim Biophys Acta. 538 445-457 Winterbourne D.J. and Mora P.T.
(1978) J Biol Chem. 253 5109-5120 (1981) ibid. 256 4310-4320 Keller
L. et al. (1980) Biochemistry. 19 2529-2536 Fransson L.-. and
Havsmark B. (1982) Carbohydr Res. 110 135-144 Stamatoglou S.C. and
Keller J.M. (1982) J Cell Biol. 96 1820-1823 Castellot J.J. et al.
(1982) J Biol Chem. 257 11256-11260 ADDENDUM
Selected Later Referenceswhich further extend knowledge of the
(heparin/HS involvement in animal cell proliferation and
transformation) research topic
Zhou H. et al. (M402, a novel heparan sulfate mimetic, targets
multiple pathways implicated in tumor progression) PloS ONE. 2011 6
(6) e21106 Chao B.H. et al. (Clinical use of the
low-molecular-weight heparins in cancer patients: focus on the
improved patient outcomes) Thrombosis. 2011 2011:530183; PMID
22084664 Borsing L. et al. (Sulfated hexasaccharides attenuate
metastasis by inhibition of P-selectin and heparanase) Neoplasia.
2011 13 (5) 445-452 Casu B. et al. (Heparin-derived HS mimics that
modulate inflammation and cancer) Matrix Biol. 2010 29 (16) 442-452
Raman K and Kuberan B (Chemical tumor biology of HS proteoglycan)
Curr Chem Biol. 2010 4 (10) 20-31 [Heparan sulfate is a profound
target for developing novel cancer therapeutics because modifying
HS chains would affect Hpa, Hsulf-1, Hsulf-2, H-sulf-2, and 3-OST
{these are key enzymes involved in HS biosynthesis and catabolism}
activity in tumor cells, which in turn would affect angiogenesis,
growth factor signal over amplification, and tumor growth, invasion
and metastasis] Barash U. et al. (Proteoglycans in health and
disease: new concepts for heparanase function in tumor progression
and metastasis) FEBS J. 2010 277 (19) 3890-3903 Lee Y.D. et al.
(Antiangiogenic activity of orally absorbable heparin derivatives
in different types of cancer cells) Pharm Res. 2009 26 (12)
2667-76; PMID 19830530; Zacharski L.R. and Lee A.Y. (Heparin as an
anticancer theraapeutic) Expert Opin Investgated Drugs. 2008 17 (7)
1029-1037 Pumphrey CY et al. (Neoglycans, carbodiimide-modified
glycosaminoglycans: a new class of anticancer agents that inhibit
cancer cell proliferation and induce apoptosis) Cancer Res. 2002 62
(13) 3722-3728 Engelberg H. Cancer. 1999 85 (23) 257-272 [Heparin
is a potential anti-cancer drug] Cf. e.g. Goldberg I.D. Ann N Y
Acad Sci 1986 463 289-291 Coombe D.R. and Kett W.C. (Heparan
sulfate-protein interactions: therapeutic potential through
structure-function insights) Cell Mol Life Sci. 2005 62 410-424
[Cf. also the later review by Casu et al. loc. cit.) is of
especially relevance as it outlines why GAGs and particularly
heparin/heparin -HS-like structures are now attracting considerable
interest as a source of new therapeutics for the treatment of
infectious diseases, inflammation and allergic diseases and
cancers; attempts to provide a critical review of the historical
development emphasises the complexity of the biochemistry of HS
(which is confirmed to be a major master system which inter alia
controls embryo development wound healing, hemostasis and the
immune system) and points out that in vitro
studies may not reproduce the in vivo conditions especially as
regards the present of metal cation cofactors and pH both of which
can have profound effects on the microstructure of HS chains on
which outcome of the interactions with the target proteins depend].
ANGIOGENESIS Ritchie J.P. et al., (SST0001, a chemically modified
heparin, inhibits myeloma growth and angiogeneis via disruption of
the heparanase/syndecan-1 axis) Clin Cancer Res. 2011 17 (6)
1382-1393 Logie J.J. et al. (Glucocorticoid-mediated inhibition of
angiogenic changes in human endothelial cells is not caused by
reductions in cell proliferation or migration) PloS ONE. 2010 5
(12) e14476; [Anti-angiogenic actions of glucocorticoids may be in
part mediated by induction of thrombospondin-1 (TSP-1); this in
turn implicates a key role of HS in this process as cf. Feitsma K.
et al. who had indicated in J Biol Chem. 2000 275 (13) 9396-9402
(Interaction of thrombospondin-1 and heparan sulfate from
endothelial cells. The microstructure of the HS cell surface
binding sites for thrombospondin-1(TSP-1) (which are responsible
for TST-1 endocytosis) contains a trisulfated 2-Osulfated iduronic
acid-N-sulfated 6-O-sulfated glucosamine disaccharide unit which is
distinct from the HS structure which is required for e.g. basic
fibroblast growth factor binding]. Jakobsson L. et al., (Heparan
sulfate in trans potentiates VEGFR-mediated angiogenesis)
Developmental Cell. 2006 10 625-634[Cf. Medical News Today
(www.medicalnewstoday.com/articles/43115.php (New discovery about
role of sugar in cell communication,,, A research team from Uppsala
Univeristy has uncovered an entirely new mechanism for how
communication between cells
is regulated. By functioning like glue, a certain type of sugar
in the body can make cell communication more effective and
stimulate the generation of new blood vessels. The discovery paves
the way for the development of drugs for cancer and rheumatism, for
example)]Linhardt R.J. (Heparin-induced cancer cell death) Chem
Biol. 2004 11 (4) 420-422 Blackhall F.H. et al. (Binding of
endostatin to endothelial HS shows a differential requirement for
specific sulfates) Biochem J. 2003 375 (1) 131-139 [Endostatin is
believed to inhibit angiogenesis (and hence tumorigeneis) by a
mechanism which appears to involve the binding of endostatin to HS
and for which 6-O sulfates played a dominant role in site
selectivity]; Folkman J. (Angiogeneiss inhibition and tumor
regression caused by heparin or a heparin fragment in the presence
of cortisol) Science. 1983 221 719-725; Cf. Crum R. et al., (A new
class of steroids inhibits angiogenesis in the presence of heparin
or HS fragments) Ibid., 1985, 230, 1375-1378 Cf. Schachtschabel
D.O. and Sluke G. (Effect of cortisol on glycosaminoglycan
synthesis and growth of diploid, human fibroblasts (WI-38) in
relation to in vitro aging) Z Gerontol. 1984 17 (3) 141-149 PMID
6475191 [Contrary to the medium the pattern of the cell surface
GAGs was changed by 1.4x10-7M cortisol with an increase in HA
synthesis and a decrease in that of sulfated GAGs; this effect of
cortisol is equivalent to a counter aging influence]
HEPARIN AFFIN REGULATORY PEPTIDE (HARP) [Pleiotrophin] Vacherot
F. et al., (Involvement of heparin affin regulatory peptide in
human prostate cancer) Prostate. 1999 38 126-136 Cf. Heroult M et
al. (HARP binds to VEGF and inhibits VEGF-induced angiogenesis)
Oncogene. 2004 23 1745-1753 Lee T-Y. Folkman J. and Javaherian K.
(HSPG (heparan sulfate proteoglycan)-binding peptide corresponding
to the exon 6a-encoded domain of VEGF (vascular endothelial growth
factor [VEGF]) inhibits tumor growth by blocking angiogenesis in
murine model) PloS ONE. 2010 5 (4) e9945; Cf. Chen J.-L et al.
(Effect of non-anticoagulant N-desulfated heparin on expression of
vascular endothelial growth factor (VEGF), angiogenesis and
metastasis of arthotopic implantation of human gastric cancer}
World J Gastroenterol. 2007 13 (3) 457-461 [N-desulfated heparin
inhibits tumor metastasis and angiogeneis via an inhibition of the
expression of VEGF (Possible Therapeutic Potential of
(Non-Animal-Sourced) HEPARINOIDS (HEPARIN-LIKE SULFATED
POLYSACCHARIDE) Zaslau S et al., Amer J Surg. 2006 192 (5) 640-643
(Pentosan polysulfate (Elmiron): In vitro effects on prostate
cancer cells regarding cell growth and vascular endothelial growth
factor production); [This heparinoid is a sulfated beech wood xylan
also known as SP54] Cf. Noda H et al. (Antitumor activity of
polysaccharides and lipids from marine algae) Nippon Suisan
Gakkaishi 1989 55 (7) 1265-1271 EXT (Heparan sulfate related) TUMOR
SUPPRESSOR Kitagawa H. et al. (The tumor suppressor EXT-like gene
EXTL2 encodes a key enzyme for the chain initiation of heparan
sulfate) J Biol Chem. 1999 274 (20) 13933-13937; Lind T. et al.
(The putative tumor suppressors EXT1 and EXT2 are
glycosyltrqansferases required for the biosynthesis of heparan
sulfate) J Biol Chem 1998 273 (41) 26265-26268 Rahmoune H. et al.
Biochem Soc Trans. 1996 24 (3) 355S [While the usual effect of
cellular transformation is a lower production of heparan sulfate of
decreased degree of sulfation, cellular transformation can also be
accompanied by an augmentation of heparan sulfate biosynthesis
(with increasing cell surface as well as culture medium released
heparan sulfate) relative to normal cells)] Cf. Biochem J. 1998 273
33 21111-21114 [A MCF-7 tumor cell HS microstructure which binds
laminin-1 (implicated in tumor-host adhesion) was identified
(IdoA(2-O-SO3-)-GlcNSO3-(6-O-SO3-)]5[IdoA(2-O-SO3-)-AManR(6S-O-SO3-was
generated using ahydrazinolysis/deaminative procedure which cleaves
deacetylated N-acetylglucosaminic bonds).
Liuzzo J.P. and Moscatelli D. (Human leukemia cell lines bind
basic fibroblast growth factor (FGF) on FGF receptors and HS: Down
modulation of FGF receptors by phorbol ester) Blood. 1996 87 (1)
245-255
HEPARAN SULFATE AT CELL NUCLEUS Buczek-Thomas J.A. et al.
(Inhibition of histone acetyltransferase by glycosaminoglycans) J
Cell Biochem. 2008 105 (1) 108-120 Hsia E. et al. (Nuclear
localization of basic fibroblast growth factor is mediated by HS
proteoglycans through protein kinase C signaling) J Cell Biochem.
2003 88 (6) 1214-1225 Richardson T.P. et al. (Regulation of HS
protoglycan nulcear localization by fibronectin) J Cell Sci. 2001
114 (9) 1613-1623 HEPARANASE (Effect at Nucleus) Purushothaman A et
al., (Heparanase-mediated loss of nuclear syndecan-1 enhances
histone acetyltransferase (HAT) activity to promote expression of
genes that drive an aggressive phenotype J Biol Chem. 2011 286 (35)
30377-30383 Yang Y. et al. (Heparanase enhances local and systemic
osteolysis in multiple myeloma by upregulating the expression and
secretion of RANKL) Cancer Res. 2010 70 (21) 8329-8338 Chen L. and
Sanderson R.D. (Heparanase regulates levels of syndecan-1{HS
proteoglycan} in the nucleus) PloS ONE. 2009 4 (3) e4947 [Although
HS function within the nucleus is not well understood there is
emerging evidence that it may act to repress transcriptional
activity] Mani K et al. (Tumor attenuation by
2(hydroxynapthyl)--D-xylopyranoside requires priming of heparan
sulfate and nuclear targeting of the products) Glycobiology. 2004
14 (5) 387-397[N.b. the HS oligomers which were found to signal to
the nucleus in these studies showed anhydroMan end groups. These
are formed during (nitric oxide ascorbate Cu/Zn facilitated)
nitrosative cleavage i.e. the (partly) non-enzymic cleavage of HS
(to give putative hormone-like HS fragments) from un-substituted
GlcNH2 groups in HS pre-primed for nitrosative cleavage. (While
such structures are known to occur in HS although the mechanism of
their insertion e.g. during primarly biosynthesis details are still
unknown but putatively may aberrantly be augmented as a result of
non-enzymic de-N sulfonation during acidosis or redox metal ion
dyshomeosasis of precursor GlcN-SO3- groups. Or perhaps by other
mechanisms which putatively contribute to the aetiologies of
neoplasia and other degenerative diseases}]
HEPARANASE - GROWTH FATOR PHOSPHORYLATIION Cohen-Kaplan V. et
al., (Heparanase augments epidermal growth factor receptor
phosphorylation: correlation with head and neck tumor progression)
Cancer Res. 2008 68 (24) 10077-85 HEPARANASE -METASTASIS Cohen E.
et al. (Heparanase is overexpressed in lung cancer and correlates
inversely with patient survival) Cancer. 2008 113 (5) 1004-1011;
Faye C. et al.
(Molecular interplay between endostatin, integrins and heparan
sulfate) J Biol Chem. 2009 284 (33) 22029-22040 Liu D et al. (Tumor
cell surface heparan sulfate as cryptic promoters or inhibitors of
tumor growth and metastasis) PNAS USA 2002 99 (2) 568-573 [Specific
different HS microstructure mixtures generated in vivo by exogenous
heparinase apparently signal for opposite growth effects on tumor
cells was suggested by the observation of the effect of difference
between heparinases I and III when injected into mice with B16BL6
melanoma; while the HS oligomer mixture arising from heparinase III
digestion caused tumour cell inhibition that produced by heparinase
I digestion caused tumor cell growth to be enhanced] Vlodavsky I
and Friedman Y. (Molecular properties and involvement of heparanase
in cancer metastasis and angiogenesis) J Clin Invest. 2001 108 (3)
341-347 CELLULAR IMMUNE ANTI-TUMOR RESPONSE Dziarski R.
(Enhancement of mixed leukocyte reaction and cytotoxic antitumor
responses by heparin) J Immunol. 1989 143 (1) 356-365 INORGANIC
CALCIUM ION : COFACTOR IN HEPARAN SULFATE ACTION Ca2+ etc.
chelation, heparan sulfate/chondroitin sulfate ratio METASTASIS Cf.
Tmr J et al. (Modulation of heparan-sulfate/chondroitin-sulfate
ratio by glycosaminoglycan biosynthesis inhibitors affects liver
metastatic potential of tumor cells) Int J Cancer. 1995 62 755-761
[Ethane-1-hydroxyl-1-1-diphosphonate [EHDP] a well tolerated
pharmaceutical (and a Ca2+ binding ligand) and other (different
mechanism) GAG biosynthesis inhibitors, were apparently able to
diminish tumor metastasis (by putatively Ca2+ dependent) inhibition
of heparan sulfate biosynthesis. It should be noted that EHDP and
related bisphosphonates osteoporosis therapeutic use also has been
indicated to produce an extended life expectance by an unknown
mechanism; it should also be noted that bisphosphonates per se have
been reported to demonstrate anti-metastatic effects in e.g. in
prostate cancer cf. e.g. Montaque R et al., Eur Urol. 2004 46 (3)
389-401] Kan M. et al. J Biol Chem. 1996 271 26143-26148 [Divalent
metal ions are essential cofactors for basic fibroblast growth
factor assembly] for correct interaction between heparan sulfate
and L-selectin as well as 2 and 3 integrins and for annexinV
assembly on cell surfaces]; Valencia-Snchez A. et al. Mol Androl.
1995 7 (1,2) 57 [Heparan sulfate Ca2+ flux control during
capacitation and modulation of acrosome reaction by heparin]
Takeuchi Y. et al. J Biol Chem. 1990 265 (23) 13661-13668
[Extracellular Ca2+ concentration regulates the distribution and
transport of heparan sulfate proteglycans and heparan fragments in
a rat parathyroid cell line] Vandewalle B. et al. J Cancer Res Clin
Oncol. 1994 120 (7) 389 Ca2+ enhanced HS proteoglycan activity
which modulate tumor cell growth Hayashi M. and Yamada K.M. J Biol
Chem. 1982 257 5263-5267 [Divalent cations are required for heparin
binding to fibronectin] Boehm T. et al. (Zinc binding of endostatin
is essential for its anti-angiogenic activity)
Biochem Biophys Res Commun. 1990 252 (1) 190-194;The roles of
Ca2+ and other metal ions in the inorganic biochemistry of heparan
sulfateallows for a system of Ca2+ Zn2+, Cun+ etc. activity
regulation (and perturbation of this toxic Mn+ metal ions) could be
relevant inter alia to a fuller understanding of how GAGs
contribute to animal tissue homeostasis and non-specific immune
protection and wound healing.
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