G-1-P Glycogen(n) UDP-Glucose Glycogen(n-1) Glycogen(n-1) UTP PP 2P
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
G-1-P
Glycogen(n)
UDP-GlucoseGlycogen(n-1)
Glycogen(n-1)
UTPPP 2P
Other tissues, like the heart, may alter this pattern.
Citric Acid Cycle (chapter 21)- Review Fates of Pyruvate
- TCA Cycle Overview
- Source of Acetyl~SCoA
- Pyruvate Dehydrogenase Complex (PDC)
- Reactions / Structure / RegulationEnzymes of the Citric Acid Cycle
- Reactions / Energy Summary / Amphibolic Nature
Glyoxylate Cycle (chapter 23-2)- Glyoxysome / Mitochondrion Enzymes
Page
582
C6H12O6 + 6 O2 6 CO2 + 6 H2O ∆Go’ = -2823 kJ/mol
C6H12O6 2 C3H6O3 ∆Go’ = -196 kJ/mol
Overview of the LINKING step and the TCA cycle. Details will follow.
The University of Texas has played a prominent role in the discovery of
vitamins in metabolism
Words Coined by Roger J. WilliamsPantothenic acid, 1933A B-vitamin. (Greek pantothen = “from everywhere”; now known to apply equally well to many other nutrients)Williams, R. J., Lyman, C. M., Goodyear, G. H., Truesdail, J. H. and Holaday, D. Pantothenic Acid, A Growth Determinant of Universal Biological Occurrence. J. American Chemical Society, 1933; 55:2912-27.
Folic acid, 1941A B-vitamin. (Latin folium = leaf)Mitchell, H. K., Snell, E. E. and Williams, R J. The Concentration of “Folic Acid.” J. American Chemical Society,1941; 63:2284.
Avidin, 1941A protein in raw egg white that avidly binds biotin (a B-vitamin), making it unavailable. Eakin, R. E., Snell, E. E. and Williams, R. J. The Concentration and Assay of Avidin, the Injury-Producing Protein in Raw Egg White. J. Biological Chemistry, 1941; 140:535-43
Two of the three forms of vitamin B6, lipoic acid, avidin, folinic acid, synthesis of vitamin B12, and pioneering work on inositol.Roger J. Williams
(1893-1988)
William Shive
(1916-2001)
University of Texas
Biochemical Institute- vitamin discovery
Page
770
Lester J. Reed
(UT 1948-1997)
E1(TPP) E2(Lipoic Acid) E3(FAD)
Eli Lilly Award - 1958Merck Award - 1994
Pyruvate HSCoA NAD+
NADHCO2 Acetyl~SCoA
Figure 21-6 The five reactions of the PDC
Mitochondria: Site of the linking step and the TCA cycle
This organelle has an oxidizing environment, and interesting evolutionary history
The “linking step”: PDCBe sure to take your vitamins: Five cofactors are used in the PDC
Page
769
Figure 21-3a: Electron micrographs of the E. coli pyruvate dehydrogenase multienzyme complex. (a) The intact complex, (b) dihydrolipoyltransacetylase (E2) “core”.
Five Reactions of the PDC
Overall linking step reaction is misleadingly simple:
Pyr + NAD+ + CoA AcCoA + NADH + CO2
E1 uses a TPP cofactor. In PDC the hydroxyethyl TPP is not released as an aldehyde, as in pyr decarboxylase, but passed to lipoic acid on E2.
Figure 17-27Reaction mechanism of pyruvate decarboxylase.
Page
605
Figure 21-8 Domain structure of the dihydrolipoyltransacetylase (E2) subunit of the PDC.
Page
773
E2
E2 is the PDC core enzyme; it spontaneously assembles. In bacteria it forms a trimer and sits on the 3-fold of the aggregate structure.
Figure 21-12a: X-Ray structure of E1 from P. putidabranched-chain a-keto acid dehydrogenase. A surface diagram of the active site region shows TPP in a deep cleft that can be reached by the mobile E2 arm system.
Page
776
TPP
E1
Lipoyllysine arm is very mobile
Ac-lipoamide reaches active site with CoA
Reduced lipoic acid is re-oxidized by E3
Page
777
E3
Figure 21-13a: X-Ray structure of dihydrolipoamidedehydrogenase (E3) from P. putida in complex with FAD and NAD+ shows physical arrangement of redox pair.
Figure 21-14Catalytic reaction
cycle of dihydrolipoyl
dehydrogenase.
Page
778
E3
Page
780
Figure 21-16The reaction transferring an electron pair from dihydrolipoyl dehydrogenase’s redox-active disulfide in its
reduced form to the enzyme’s bound flavin ring.
E3
Figure 21-11c: Electron microscopy–based images of the bovine kidney pyruvate dehydrogenase complex at ~35 Å resolution. (c) A cutaway diagram as in Part b but with E3 dimers (Fig. 21-13a) shown at 20 Åresolution (red) modeled into the pentagonal openings of the E2 core.
Page
774
Mammalian Complex:
60 E2 (52 kDa)
30 E1(α2β2 154 kDa)
12 E3 dimers (110 kDa)
+ ~6 binding proteins
+ ~3 kinase (~62 kDa)
+ ~3 phosphatase (~100kDa)
PDC is regulated by products
High concentrations of NADH and/or AcCoAcan run reactions 3 & 5 backward
Figure 21-17b Factors controlling the activity of the PDC.(b) Covalent modification in the eukaryotic complex.
Page
781
On to the TCA cycle
Page
766
Hans Krebs
1937 C4C2
C6
C6
C4
C5C4
Simplified TCA Cycle
Figure 21-18a: Conformational changes in citrate synthase. (a) Space-filling drawing showing citrate synthase in the open conformation. (b) closed, substrate-binding conformation.
Page
782
TCA Cycle Enzymes
Figure 21-19 : Mechanism and stereochemistry of the citrate synthase reaction.
Aha! Enolate anion as a nucleophile.
Aconitase removes, and then adds
back, water
Aconitase has a 4 Fe-4S cluster. The FeS cluster carries out NO redox function, but interacts directly with an organic substrate.
In humans, a CYTOSOLIC form doubles as an iron monitor, regulating transcription from iron response elements (IRE).
Mechanism and stereochemistry of the aconitase reaction.Pa
ge 7
84
Figure 21-21Probable reaction mechanism of isocitrate
dehydrogenase.
Page
785
Oxidation creates a carbonyl electron sink to facilitate β-decarboxylation
The five reactions of the KGDC are similar to those of PDC,and the structure of KGDC is similar to the 24-mer PDC.
Figure 21-22a: Reactions catalyzed by succinyl-CoA synthetase. Formation of succinyl phosphate, a “high-energy” mixed anhydride.
Page
787
succinyl-CoA synthetase: the only direct phophorylation in TCA - step 1
Figure 21-22b: Reactions catalyzed by succinyl-CoA synthetase. Formation of phosphoryl–His, a “high-energy” intermediate.
Page
787succinyl-CoA synthetase - step 2
Figure 21-23Covalent attachment of FAD to a His residue of succinate dehydrogenase.
Page
787
Succinate dehydrogenase
- membrane bound enzymeFADH2
FAD
Standard Free Energy Changes (∆G°’) and Physiological Free Energy Changes (∆G) of TCA Cycle Reactions.
Page
790
Simplified TCA Cycle
Page
791
PDC
KGDC
ICDH
Cit Synth
Regulation of the citric acid cycle.
Flux through the system is largely controlled by concentrations of reactants and PRODUCTS, espNADH, at irreversible steps.
Another representation
of TCA regulation
, NADH
Page
793
Amphibolicfunctions of the citric acid cycle.
The intermediates of the TCA cycle are chemically very useful and are drawn off for a variety of tasks. Without CARRIERS, the cycle slows
Anaplerotic Reactions:
1) Pyruvate Carboxylase (has requirement for AcCoA– that makes sense!)
pyr + CO2 + ATP OAA + ADP
2) Malic E
pyr + CO2 + NADPH L-Mal + NADP+
3) Transamination Reactions:
Ala Pyr
Asp OAA
Glu KG
Figure 23-10:The glyoxylate cycle. Why plants can convert lipid to sugar and you can’t.
Page
851
The Glyoxylate shunt, found in plants and some microbes, allows synthesis of glucose from lipid derived AcCoA. Two novel enzymes short work with TCA to create the shunt.
Radioisotopes greatly facilitate metabolic mapping.
Putting label at differing places
allows researchers to follow enzyme activities and
construct pathways.
14C Dating14C is generated from N2 in atmosphere at ~constant rate. Living systems take it up, until they die. From then on, normal fraction of 14C decays with half live ~5700 years.
Related Documents
