Author: Robert Lyons, Ph.D., 2008 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution – Share Alike 3.0 License: http://creativecommons.org/licenses/by-sa/3.0/ We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact [email protected]with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use. Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
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Author: Robert Lyons, Ph.D., 2008 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution – Share Alike 3.0 License: http://creativecommons.org/licenses/by-sa/3.0/ We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact [email protected] with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use. Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
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M1 Renal: Nitrogen Metabolism (and Related Topics)
Defects are diagnosed based on the metabolites seenin the blood and/or urine.
CPSD
OTCD
ASD
ALD
AD
No elevation except ammonia; diagnosed by elimination.Elevated CP causes synthesis of OrotateElevated citrullineElevated argininosuccinateElevated arginine
Inherited Defects of Urea Cycle Enzymes: Diagnosis
Liver mitochondrion
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
(+)
Arginine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
O
Citrulline
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH C
O
Citrulline
2ATP + HCO +3
NH2 C
O
3OPO(-)
Carbamoylphosphate
Pi
2ADP + Pi
O CCH C
H
2 2 2
aspartate
(-) (-)CO
i
ATP
AMP + PP
C
H
OOC CH2
NH3
(+)
(-)CH
2CH
2NH C
O CCH C
H
2 2 2(-) (-)CO
(+)
Argininosuccinate
Liver cytoplasm
O C C CH
2 2(-) (-)CO
H
Fumarate
H O2
CO
Urea
NH2
NH2
NH2
NH3
NH2
NH2
NH2
NH2
NH2NH2
1
5
4
3
2
R. Lyons
C P S I is S t im u la ted by N A G
H O C
O
O
A T P
A D P
P
N H
P
( -) H O C
O
O
bi ca rb o na tec a rb on y l
p ho s ph at e i
3
H O C
O
N H2
c ar ba m at e
A T P
A D P
O C
O
N H2
P
c ar ba m oy l
p ho sp h at e
g lu t am ate
C
H
O O C C H2
N H3
( +)
( - )
C H2C
O
O H+ CoA -
C
H
O O C C H2
N H
( - )
C H2C
O
O H
C O
C H3
C O
C H3
a cety l Co A N -acety l g lu t am a te(N AG )
N -a ce ty lg lu ta m a tesy n th e tase
( re pe a t in g the f igu re from pa ge 3 o f y ou r h an do u t)
R. Lyons
Liver mitochondrion
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
(+)
Arginine
C
H
OOC CH2
NH3(+)
(-) CH2CH
2NH C
O
Citrulline
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH C
O
Citrulline
2ATP + HCO +3
NH2 C
O
3OPO(-)
Carbamoylphosphate
Pi
2ADP + Pi
O CCH C
H
2 2 2
aspartate
(-) (-)CO
i
ATP
AMP + PP
C
H
OOC CH2
NH3
(+)
(-)CH
2CH
2NH C
O CCH C
H
2 2 2(-) (-)CO
(+)
Argininosuccinate
Liver cytoplasm
O C C CH
2 2(-) (-)CO
H
Fumarate
H O2
CO
Urea
NH2
NH2
NH2
NH3
NH2
NH2
NH2
NH2
NH2NH2
1
5
4
3
2
R. Lyons
Clinical Management of Urea Cycle Defects
• Dialysis to remove ammonia • Provide the patient with alternative ways to excrete
nitrogenous compounds: • Levulose - acidifies the gut • Low protein diet
* Intravenous sodium benzoate or phenylacetate * Supplemental arginine
Ornithine
Arginine
Citrulline
i
ATP
AMP+PPArgininosuccinate
HO2
CO
UreaNH2NH2 Aspartate
Excreted by kidney
Excreted by kidney
XDietaryArginine
carbamoylphosphate
XASD
ALD
R. Lyons
Degrading the Amino Acid Carbon Backbone
Easily-degraded products after transamination:
O C CH C
H
NH3
2 2 2
aspartate
(-)COtransamination
O CCH CO
2 2 2(-)CO
oxaloacetate
(-) (-)
(+)
O C CH C
H
NH3
2 2 2
glutamate
(-)
transaminationCH C
O2 2
(-)
!-ketoglutarate
CH2
O C2
CH2
CO CO(-) (-)
(+)
CH C
H
NH3
3 2
alanine
(-)COtransamination
CH C
O3 2
(-)CO
pyruvate(+)
We also already know how to degrade Glutamine: Glutamine ----------------> glutamate + ammonia Asparagine ---------------> aspartate + ammonia
…and by analogy, how to degrade Asparagine:
glutaminase
asparaginase
glutaminase
R. Lyons
Many amino acids are purely glucogenic: Glutamate, aspartate, alanine, glutamine, asparagine,…
Some amino acids are both gluco- and ketogenic: Threonine, isoleucine, phenylalanine, tyrosine, tryptophan
Amino Acids are categorized as ‘Glucogenic’ or ‘ketogenic’ or both.
The only PURELY ketogenic Amino Acids: leucine, lysine
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH NH
2C
NH2(+)
Arginine
Urea (viathe urea cycle)
C
H
OOC CH2
NH3(+)
(-)CH
2CH
2NH3
(+)
Ornithine!-ketoglutarate
glutamate
C
H
OOC CH2
NH3
(+)
(-)CH
2C
glutamate - 5 - semialdehyde
O
H
NAD(P)
NAD(P)H
(+)
C
H
OOC CH2
NH3(+)
(-)CH
2C
glutamate
O
OH
! - ketoglutarate
NH
(+)OOC(-)
Proline
glutamine
C
H
OOC CH2
NH3(+)
(-)CH
2C
O
NH2
H O2
NH3
Amino acids with 5-carbon backbones tend to form α-ketoglutarate
R. Lyons
C
H
OOC NH3(+)
(-)
H
Glycine
NAD NADH(+)
THF N -N - methylene THF5 10
+CO NH4
(+)
2
CH
OOC NH3(+)
(-)2
GlycineTHF N -N - methylene THF5 10Serine
CHOOC NH3(+)
(-)
CH OH2
GlycineSynthase:
SerineHydroxymethyl-transferase:
Serine
CHOOC NH3(+)
(-)
CH OH2
H O2
COOC NH3
(+)(-)
CH2
COOC NH2
(+)(-)
CH3
COOC(-)
CH3
H O2
NH4
(+)
OSerine
Dehydratase:
Degradation and Biosynthesis of Serine and Glycine
R. Lyons
C
H
COOCH2
NH3
(+)
(-)CH2
Methionine
Serine
C
H
COOCH2
NH3(+)
(-)HO
SCH3
C
H
COOCH2
NH3(+)
(-)CH2
S-Adenosyl Methionine
SCH3
ATP +H O2
PPi +Pi
(+)
CH2
O
HH H
HOH OH
Adenine
C
H
COOCH2
NH3
(+)
(-)CH2
Homocysteine
HS
C
H
COOCH2
NH3(+)
(-)CH2
S-Adenosyl Homocysteine
HS(+)
CH2
O
HH H
HOH OH
Adenine
BiosyntheticMethylation
reaction
Methyl acceptor
Methylated acceptor*see examples
C
H
COOCH2
NH3(+)
(-)
Cysteine
HS
(remainder ofhomocysteine
degradedfor energy)
tetrahydrofolate
N5 methyltetrahydrofolate
Methionine Cycle And Biological Methyl Groups
R. Lyons
Phenylalanine and Tyrosine
CH2 CH COO
NH3(+)
(-)
Phenylalanine
Tetrahydrobiopterin + O2Dihydrobiopterin + H2O
CH2 CH COO
NH3(+)
(-)
Tyrosine
HO
Homogentisate
Enzyme:Phenylalaninehydroxylase
Enzyme:homogentisatedioxygenaseCH2 C COO
(-)
Phenylpyruvate
O
Phenylketonuria(no phenylalanine
hydroxylase)
(Normal path shown in black, pathological reaction shown in red)
(you don’t need to know the rest)
Deficiency: Alkaptonuria “Ochronosis”
R. Lyons
Branched Chain Amino Acids
Isoleucine Leucine Valine
CH COO(-)
NH3(+)
CHCH2CH3
CH3
CH COO(-)
NH3(+)
CHCH 2CH3
CH3
CH COO(-)
NH3(+
)
CHCH3
CH3
C COO(-)
O
CHCH2CH3
CH3
C COO(-)
CHCH 2CH3
CH3
C COO(-)
CHCH3
CH3
O O
C
O
CHCH2CH3
CH3
CCHCH 2CH3
CH3
C S-CoACHCH3
CH3
O O
NAD, CoASH+
NADH +CO
2
NAD, CoASH+ NAD, CoASH+
NADH + CO2 NADH + CO2
S-CoAS-CoA
!"KG !"KG !"KG
Glu Glu Glu
---------------- Transamination ----------------
--- Branched-chain !-keto acid dehydrogenase ---
(continues on to degradation path similar to #-oxidation of fatty acids)R. Lyons
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