author: robert lyons, ph.d., 2008 license: unless otherwise noted, this material is made available...
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Author: Robert Lyons, Ph.D., 2008
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M1 Renal:Nitrogen Metabolism (and Related Topics)
Fall 2008
• Amino Acid Metabolism (Nitrogen metabolism)• Folate Metabolism (“One-Carbon pathways”)• Nucleotide Metabolism
Dr. Robert LyonsAssistant Professor, Biological Chemistry
Director, DNA Sequencing CoreWeb: http://seqcore.brcf.med.umich.edu/mcb500
Supplementary study material on the Web: http://seqcore.brcf.med.umich.edu/mcb500
R. Lyons
Glu, Gln,
A sp , N H 3
Amino Acid metabolismFolate metabolism
Nucleic Acid metabolism
Methylene
THF
Met
Cyc le
Purines Pyrimidines
U ric A cid
Urea
A mino acids
DNA
RN A
( energy )
TCA Cycle
f um arat e
oxa loac etat e
R. Lyons
Protein Degradation:
• Endogenous proteins degrade continuously- Damaged- Mis-folded- Un-needed
• Dietary protein intake - mostly degraded
Nitrogen Balance - expresses the patient’s current status - are they gaining or losing net Nitrogen?
Transaminases Collect Amines
Genera l reac t io n o v erv iew :
C
H
R COO
NH2
aminoacid
C
H
R COO
NH2
aminoacid
(typicall y gl utamate)
12CR COO
Oα - k e t o
a c i d( t y p i c a l l y
a l pha - k e t o g l u t a r a t e )
( - )+ +
2CR COO
O
α - k e t oa c i d
( - )
1
( - ) ( - )
Det a ils o f reac t io n m ec hanism :
C
H
R COO
NH
C
H
R COO
N
N
CH
O
CH
CH
OHOP
py r i d o x a lpho s p ha t e
a mi noa c i d
+
H O2
3
2
CH
CH
CH
OHOP
3
2
2
C
H
R COO
N
CH
CH
CH
OHOP
3
2
+
H
+
+
C
H
R COO
N
CH
CH
CH
OHOP
3
2
+
CR COO
NH
CH
O
CH
CH
OHOP
py r i do x a mi neph o s pha t e
+
3
2
2
+
H
α - k e t oa c i d
( - )( - ) ( - )
( - )
( - )
NH
NH
NH N
H
R. Lyons
NH
N
CH
CH
CH
OHOP
pyridoxaminephosphate
3
2
2
H
+
H
+ CR COOO
α- ket oaci d
N
CHO
CH
CH
OHOP
pyr i doxalphosphat e
3
2
H
++ C
H
R COO
NH2
ami noaci d
( - )
Transfer the amine back to an acceptor α-keto acid
R. Lyons
Some amino acid + α-ketoglutarate some alpha keto acid + Glutamate
In other words, alpha-ketoglutarate is the preferredacceptor, and Glutamate is the resulting amino acid:
In peripheral tissues, transaminases tend to formGlutamate when they catabolize amino acids
Glutamate can donate its amines to form other amino acids as needed
Glutamate + oxaloacetate α-ketoglutarate + aspartate
A specific example - production of Aspartate in liver(described a few slides from now):
Getting Amines Into the Liver
O C CH CH C
H
NH
CO
2
2 2 2 2
glutamate
NAD(P)
NAD(P)H
O C CH CH C CO2 2 2 2
α- ket ogl ut ar at e
+ NH3
ammoni a
( - ) ( - ) ( - ) ( - )
O( mi t o)
C
H
OOC CH2
NH3
( +)
( - )CH
2COO
( - )
glutamate glutamine
C
H
OOC CH2
NH3
( + )
( - )CH
2C
O
NH2
NH3
ATP ADP Pi
+ +
Glutam ateDe hy drog ena se :
Glutam ine
Synthe tas e:
R. Lyons
In the Liver: Precursers for Urea Cycle
Glutamine is hydro lyzed to glut amate and ammonia:
C
H
OOC CH2
NH3
(+)
(-)CH
2C
glutam ate
O
OH
glutam ine
C
H
OOC CH2
NH3
(+)
(-)CH
2C
O
NH2
H O2
NH3
Glutam ate donates its am ino group to form aspartate:
Glutamate aspartateoxaloacetate
+ +
α- ket ogl ut ar at e
OC CH CH C
H
NH
CO
2
2 2 2 2( - ) ( - ) O CCH C
H
CO2 2 2
( - ) ( - ) OC CH CH C
O
CO2 2 2 2
( - ) ( - ) OCCH C
H
NH
CO
2
2 2 2( - ) ( - )
O
Glutamate-aspartate aminotransferase:
.
.
Ammonia can also be formed by the glutamate dehydrogenase reaction and several other reactions as well.
R. Lyons
Liver mito chondrion
C
H
OOC CH2
NH3
( +)
( -)CH
2CH
2NH3
(+ )
O rn ithin e
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH3
( + )
O rnith ine
C
H
OOC CH2
NH3
(+ )
( - )CH
2CH
2NH C
( +)
A rg inine
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH C
O
C itru lline
C
H
OOC CH2
NH3
(+ )
(- )CH
2CH
2NH C
O
C itru lline
2ATP + HCO +3
NH 2 C
O
3OPO
( -)
C arb am o y l
p h osp hate
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 C CH C
H
2 2 2
(- ) ( -)CO
(+ )
A rg inin o su ccin ate
Liver cytoplasm
O C C CH
2 2(- ) (- )
COH
F um arate
H O2
C
O
U rea
NH 2
NH 2
NH 2
NH 3
NH 2
NH 2
NH 2
NH 2
NH 2NH 2
1
5
4
3
2
R. Lyons
C arbam o y l pho s phat e sy nthe tas e I
HO C
O
O
ATP
ADP
P
NH
P
(- ) HO C
O
O
bicarbonatecarbonyl
phosphate i
3
HO C
O
N H2
carbamate
ATP
ADP
O C
O
NH2
P
carbamoyl
phosphate
R. Lyons
O rnit h ine T rans carb am o y las e
C
H
OOC CH2
NH3
(+ )
( -)CH
2CH
2NH3
(+ )
O rn ith in e
C
H
OOC C H2
NH3(+ )
(- )CH
2CH
2NH
2NHC
O
C itrullin e
NH2C
O
3OPO( -)
C arb am o y lp ho sp hate
P i
CH2NH3
(+ )
R. Lyons
A rg in ino suc c inate s ynt he t as e
O C CH
C
H
NH2
2 2 2
aspartate
( - ) (- )CO
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH
2NHC
O
C itrulline
iATP AMP + PP
C
H
OOC CH2
NH3
( +)
( - )C H
2CH
2NH C NH
O C CH C
H
NH2
2 2 2(- ) ( - )CO
2
( +)
A rg inin o succin ate
R. Lyons
A rg inino s ucc inat e lyase
C
H
OOC CH2
N H3(+ )
( -)CH
2CH
2NH NH
2C
NH2
(+ )
A rg inin e
C
H
OOC CH2
NH3
(+ )
( -)CH
2CH
2NH C NH
O C CH C
H
NH2
2 2 2(- ) ( -)CO
2
(+ )
A rg in in osu ccin ateO C C C
H
2 2( -) ( - )C O
H
Fu m ara te
R. Lyons
A rg inas e
C
H
OOC CH2
NH3( + )
( - )CH
2CH
2NH
3
( + )
O rnith ine
C
H
OOC CH2
NH3(+ )
( -)CH
2CH
2NH NH
2C
NH2
( +)
A rg inin eNH
2C
O
NH2
U rea
H2O
R. Lyons
Liver mito chondrion
C
H
OOC CH2
NH3
( +)
( -)CH
2CH
2NH3
(+ )
O rn ithin e
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH3
( + )
O rnith ine
C
H
OOC CH2
NH3
(+ )
( - )CH
2CH
2NH C
( +)
A rg inine
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH C
O
C itru lline
C
H
OOC CH2
NH3
(+ )
(- )CH
2CH
2NH C
O
C itru lline
2ATP + HCO +3
NH 2 C
O
3OPO
( -)
C arb am o y l
p h osp hate
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 C CH C
H
2 2 2
(- ) ( -)CO
(+ )
A rg inin o su ccin ate
Liver cytoplasm
O C C CH
2 2(- ) (- )
COH
F um arate
H O2
C
O
U rea
NH 2
NH 2
NH 2
NH 3
NH 2
NH 2
NH 2
NH 2
NH 2NH 2
1
5
4
3
2
R. Lyons
Urea Cyc le Co nnec t s t o T CA Cyc le
A rg in in e
C itru llin e
O C CH C
H
NH2
2 2 2
A spartate
( - ) ( - )CO
A rgininosuccinate
O C C CH
2 2( - ) ( - )CO
H
Fum arate
M alate
O xaloacetate
T C A C ycle
α -K etoglutarate
C itrate
U r ea
Ornithine
U r ea C ycle
R. Lyons
Getting Amines Into the Liver
O C CH CH C
H
NH
CO
2
2 2 2 2
glutamate
NAD(P)
NAD(P)H
O C CH CH C CO2 2 2 2
α- ket ogl ut ar at e
+ NH3
ammoni a
( - ) ( - ) ( - ) ( - )
O( mi t o)
C
H
OOC CH2
NH3
( +)
( - )CH
2COO
( - )
glutamate glutamine
C
H
OOC CH2
NH3
( + )
( - )CH
2C
O
NH2
NH3
ATP ADP Pi
+ +
Glutam ateDe hy drog ena se :
Glutam ine
Synthe tas e:
R. Lyons
Liver mito chondrion
C
H
OOC CH2
NH3
( +)
( -)CH
2CH
2NH3
(+ )
O rn ithin e
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH3
( + )
O rnith ine
C
H
OOC CH2
NH3
(+ )
( - )CH
2CH
2NH C
( +)
A rg inine
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH C
O
C itru lline
C
H
OOC CH2
NH3
(+ )
(- )CH
2CH
2NH C
O
C itru lline
2ATP + HCO +3
NH 2 C
O
3OPO
( -)
C arb am o y l
p h osp hate
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 C CH C
H
2 2 2
(- ) ( -)CO
(+ )
A rg inin o su ccin ate
Liver cytoplasm
O C C CH
2 2(- ) (- )
COH
F um arate
H O2
C
O
U rea
NH 2
NH 2
NH 2
NH 3
NH 2
NH 2
NH 2
NH 2
NH 2NH 2
1
5
4
3
2
R. Lyons
C P S I is St im u lat ed by N A G
HO C
O
O
ATP
ADP
P
NH
P
( -) HO C
O
O
bicarbonatecarbonyl
phosphate i
3
H O C
O
NH2
carbamate
ATP
ADP
O C
O
NH2
P
carbamoyl
phosphate
g lu tam ate
C
H
OOC CH2
NH3
( +)
( - )
CH2C
O
OH+ CoA -
C
H
OOC CH2
NH
( - )
CH2C
O
OH
C O
CH3
C O
CH3
a cetyl C o AN -acety lg lu tam a te
(N A G )
N -acetyl
g lutam ate
synthetase
(repeating the figure from page 3 o f your han do ut)
R. Lyons
Muscle
Liver
Glucose Pyruvate
Alanine
Amino acids
(Amines)
α-ketoglutarate
Glutamate
Alanine
PyruvateGlucose
bloodtransport
α-ketoglutarate
Glutamate NH3
Urea
--
R. Lyons
Arginine
Amino acids:
Alanine Glutamate
Glutamine
Transamination Deaminationpurine
deamination:
NH4
(+)
Glutamine
Alanine NH4
(+)Citrulline
NH4
(+) Urea
Muscle:
Liver:
Intestine:
Alanine
AspartateGlu
Glutamine
NH3
Kidney:
Arginine
Citrulline
Glutamine
NH4
(+)
Complicating the picture: Other tissues may be involved
R. Lyons
Why is Ammonia Toxic?
Why is Ammonia Toxic?
• Possible neurotoxic effects on glutamate levels (and also GABA)
(due to shifting equilibria of reactions involving these compounds)
Why is Ammonia Toxic?
• Possible neurotoxic effects on glutamate levels (and also GABA)
(due to shifting equilibria of reactions involving these compounds)
• Possible metabolic/energetics effects:- alpha-ketoglutarate levels- glutamate levels- glutamine
Liver mito chondrion
C
H
OOC CH2
NH3
( +)
( -)CH
2CH
2NH3
(+ )
O rn ithin e
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH3
( + )
O rnith ine
C
H
OOC CH2
NH3
(+ )
( - )CH
2CH
2NH C
( +)
A rg inine
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH C
O
C itru lline
C
H
OOC CH2
NH3
(+ )
(- )CH
2CH
2NH C
O
C itru lline
2ATP + HCO +3
NH 2 C
O
3OPO
( -)
C arb am o y l
p h osp hate
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 C CH C
H
2 2 2
(- ) ( -)CO
(+ )
A rg inin o su ccin ate
Liver cytoplasm
O C C CH
2 2(- ) (- )
COH
F um arate
H O2
C
O
U rea
NH 2
NH 2
NH 2
NH 3
NH 2
NH 2
NH 2
NH 2
NH 2NH 2
1
5
4
3
2
R. Lyons
Defects are diagnosed based on the metabolites seen
in the blood and/or urine.
CPSD
OTCD
ASDALD
AD
No elevation except ammonia; diagnosed by elimination.
Elevated CP causes synthesis of Orotate
Elevated citrulline
Elevated argininosuccinate
Elevated arginine
Inherited Defects of Urea Cycle Enzymes: Diagnosis
Liver mito chondrion
C
H
OOC CH2
NH3
( +)
( -)CH
2CH
2NH3
(+ )
O rn ithin e
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH3
( + )
O rnith ine
C
H
OOC CH2
NH3
(+ )
( - )CH
2CH
2NH C
( +)
A rg inine
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH C
O
C itru lline
C
H
OOC CH2
NH3
(+ )
(- )CH
2CH
2NH C
O
C itru lline
2ATP + HCO +3
NH 2 C
O
3OPO
( -)
C arb am o y l
p h osp hate
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 C CH C
H
2 2 2
(- ) ( -)CO
(+ )
A rg inin o su ccin ate
Liver cytoplasm
O C C CH
2 2(- ) (- )
COH
F um arate
H O2
C
O
U rea
NH 2
NH 2
NH 2
NH 3
NH 2
NH 2
NH 2
NH 2
NH 2NH 2
1
5
4
3
2
R. Lyons
C P S I is St im u lat ed by N A G
HO C
O
O
ATP
ADP
P
NH
P
( -) HO C
O
O
bicarbonatecarbonyl
phosphate i
3
H O C
O
NH2
carbamate
ATP
ADP
O C
O
NH2
P
carbamoyl
phosphate
g lu tam ate
C
H
OOC CH2
NH3
( +)
( - )
CH2C
O
OH+ CoA -
C
H
OOC CH2
NH
( - )
CH2C
O
OH
C O
CH3
C O
CH3
a cetyl C o AN -acety lg lu tam a te
(N A G )
N -acetyl
g lutam ate
synthetase
(repeating the figure from page 3 o f your han do ut)
R. Lyons
Liver mito chondrion
C
H
OOC CH2
NH3
( +)
( -)CH
2CH
2NH3
(+ )
O rn ithin e
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH3
( + )
O rnith ine
C
H
OOC CH2
NH3
(+ )
( - )CH
2CH
2NH C
( +)
A rg inine
C
H
OOC CH2
NH3
( + )
( - )CH
2CH
2NH C
O
C itru lline
C
H
OOC CH2
NH3
(+ )
(- )CH
2CH
2NH C
O
C itru lline
2ATP + HCO +3
NH 2 C
O
3OPO
( -)
C arb am o y l
p h osp hate
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 C CH C
H
2 2 2
(- ) ( -)CO
(+ )
A rg inin o su ccin ate
Liver cytoplasm
O C C CH
2 2(- ) (- )
COH
F um arate
H O2
C
O
U rea
NH 2
NH 2
NH 2
NH 3
NH 2
NH 2
NH 2
NH 2
NH 2NH 2
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+PP
ArgininosuccinateHO2
CO
UreaNH2NH2 Aspartate
Excreted by kidney
Excreted by kidney
XDietaryArginine
carbamoyl phosphate
X ASD
ALD
R. Lyons
Degrading the Amino Acid Carbon Backbone
Easily-degraded products after transamination:
O C CH C
H
NH3
2 2 2
aspartate
( - )C O
t ransa minat io nO C CH C
O2 2 2
( - )C O
ox a l o ac et a t e
( - ) ( - )
( +)
O C C H C
H
NH3
2 2 2
gl ut a ma t e
( - )
t ransam ina t io n
CH C
O2 2
( - )
α - ke t o gl ut ar at e
CH2
O C2
CH2
C O C O( - ) ( - )
( + )
CH C
H
NH3
3 2
a l a n i ne
( - )CO
t ra nsam ina t io n
CH C
O3 2
( - )C O
py r uva t e( +)
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
( +)
A rg in ine
U rea ( via
t h e u re a cy c le)
C
H
OOC CH2
NH3
( +)
( - )CH
2CH
2NH
3
( +)
Orn it hin e
α -ke t og lu t arat e
glu tam at e
C
H
OOC CH2
NH3
( +)
( - )CH
2C
glut am at e - 5 - s em iald eh yd e
O
H
NA D (P)
NA D (P)H
( + )
C
H
OOC CH2
NH3
( + )
( - )CH
2C
g lut am ate
O
OH
α - ke t o g lu t arat e
NH
( + )OOC( - )
P ro line
g lu ta min e
C
H
OOC CH2
NH3
( + )
( - )CH
2C
O
NH2
H O2
NH3
Amino acids with 5-carbon backbones tend to formαketoglutarate
R. Lyons
C
H
OOC NH3
(+ )
(- )
H
Glyc in e
NAD NADH( +)
T HF N - N - me t hy l e ne THF5 10
+C O NH4
( +)
2
CH
OOC NH3
( +)
( - )
2
Gly c ineT HF N - N - met hy l ene T HF5 10S e rin e
CHOOC NH3
( +)
( - )
CH OH2
G ly c in e
Sy n th a s e :
Se rin e
H y d ro x y m e t h y l -
t ra n s f e ra s e :
S erin e
CHOOC NH3( +)
(- )
CH OH2
H O2
CO OC NH3
( +)(- )
CH2
COOC NH2
(+ )(- )
CH3
COOC( - )
CH3
H O2
NH4
( +)
OS e rin e
D e h y d ra ta s e :
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)
te t rah yd ro fo lat e
N5 me th ylt et rah yd ro fo la te
Methionine CycleAnd BiologicalMethyl Groups
R. Lyons
P henylalan ine and T yro s ine
CH2
CH COO
NH 3
(+)
(-)
P h en ylalan in e
Tetrahydrobiopte rin + O 2
Dihydrobi opterin + H 2O
CH2
CH COO
NH 3
(+)
(-)
T yro sin e
HO
H om og entisate
En zym e:
P h en ylalan in e
h yd ro xylase
E nz ym e:
ho m o g en tisate
d ioxy g en aseCH
2C COO
(-)
P h en ylp yru vate
O
Phenylketonuria
(no phenylalanine
hydroxylase)
(N orm al path show n in black, pathological reaction show n in red)
(you don’t need to
know the rest)
Deficiency:Alkaptonuria“Ochronosis”
R. Lyons
B ran c h e d C h a in A m in o A c id s
Is o le u c in e L e u c in e V a lin e
C H C O O( - )
N H3
( + )
C HC H2
C H3
C H3
C H C O O( - )
N H3
( + )
C HC H2
C H3
C H3
C H C O O( - )
N H3
( +
)
C HC H3
C H3
C C O O( - )
O
C HC H2
C H3
C H3
C C O O( - )
C HC H2
C H3
C H3
C C O O( - )
C HC H3
C H3
O O
C
O
C HC H2
C H3
C H3
CC HC H2
C H3
C H3
C S -C o AC HC H3
C H3
O O
N A D , C o A S H+
N A D H +
C O2
N A D , C o A S H+
N A D , C o A S H+
N A D H + C O2 N A D H + C O 2
S - C o AS - Co A
α −K G α −K G α −K G
G l u G lu G l u
- - - - - - - - - - - - - - - - T r a n s a m in a t io n - - - - - - - - - - - - - - - -
- - - B r a n c h e d - c h a in α - k e t o a c id d e h y d r o g e n a s e - - -
( c o n t in u e s o n t o d e g r a d a t io n p a t h s im ila r t o β - o x id a t io n o f f a t t y a c id s )
R. Lyons
Synthesis o f Bioact ive A mines
CH 2 CH COO
NH 3
(+)
(-)
T yrosin e
HO CH2
CH COO
NH 3
(+)
(-)HO
HO
D ih ydroxyp heny lalanin e
T yro sin e
hyd ro xy lase
(L-D O PA )
HO
HO
CH2CH NH 3
(+)
2
D op am ine
CH CH NH 3
(+)
2
N o repine phrine
OH
H
HO
HO
CH CH NH
2
Ep ineph rine
OH
H
HO
HO
CH 3
R. Lyons
N
CH 2 CH COO
NH3(+)
(-) HO
N
CH2 CH COO
NH3(+)
(-)
T ryp to ph an 5 -hyd roxytryp to ph an
Tryptophan
hydroxylase
CO2
HO
N
CH2
CH NH3( +)
Sero to nin
2
PLP-dependent
decvarboxylation
NAD+
Synthesis of Bioactive Amines
R. Lyons
CH 2 CH COO
NH 3(+)
(-)
CH 2COO(-)
Glut amate
Glutamate
decarboxylase
(PLP-dependent )
CH2 CH NH3( +)
CH2COO( - )
γ-amin ob ut yric ac id
(GA BA )
2
N
NH
CH2 CH COO
NH3( + )
( -
)
Hist idine
H ist id ine
de carbo xylase
( PL P-de pe nd ent )
N
NH
CH2 CH NH3( +)
Hist amine
2
Synthesis of Bioactive Amines
R. Lyons
Glutamate, aspartate, alanine, glutamine, asparagine,(proline), glycine, serine (cysteine, tyrosine)
NON-Essential Amino Acids:
Essential Amino Acids:
Arginine (!), phenylalanine, methionine, histidine,Isoleucine, leucine, valine, threonine, tryptophan, lysine
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