CHAPTER 30: CONVERSION OF AMINO ACIDS TO SPECIALIZED Three enzymecatalyzed reactions convert cysteine to taurine,

PRODUCTS which can displace the coenzyme A moiety of cholyl-CoA to

form the bile acid taurocholic acid.
BIOMEDICAL IMPORTANCE The conversion of cysteine to taurine is initiated by its
Certain proteins contain amino acids that have been oxidation to sulfinoalanine (cysteine sulfinate), catalyzed by
posttranslationally modified to permit them to perform the nonheme Fe2+ enzyme cysteine dioxygenase.
specific functions. Decarboxylation of cysteine sulfinate by sulfinoalanine
Examples include: decarboxylase forms hypotaurine, whose oxidation by
the carboxylation of glutamate to form - hypotaurine dehydrogenase forms taurine.
carboxyglutamate, which functions in Ca2+ binding
the hydroxylation of proline for incorporation into the Glycine
collagen triple helix Many metabolites and pharmaceuticals are excreted as
the hydroxylation of lysine to 5-hydroxylysine, whose watersoluble glycine conjugates.
subsequent modification and cross-linking stabilizes Examples include:
maturing collagen fibers glycocholic acid
In addition to serving as the building blocks for protein hippuric acid formed from the food additive benzoate
synthesis, amino acids serve as precursors of diverse biologic Many drugs, drug metabolites, and other compounds with
materials such as: carboxyl groups are conjugated with glycine, which makes
Heme them more water-soluble and thereby facilitates their
Purines excretion in the urine.
Pyrimidines Glycine is incorporated into creatine, and the nitrogen and -
Hormones carbon of glycine are incorporated into the pyrrole rings and
Neurotransmitters the methylene bridge carbons of heme, and the entire glycine
Biologically active peptides molecule becomes atoms 4, 5, and 7 of the purines.
Histamine plays a central role in many allergic reactions.
Neurotransmitters derived from amino acids include: Histidine
-aminobutyrate Decarboxylation of histidine to histamine is catalyzed by:
5-hydroxytryptamine (serotonin) the pyridoxal 5-phosphate-dependent enzyme histidine
Dopamine decarboxylase
Norepinephrine A biogenic amine that functions in allergic reactions and
Epinephrine gastric secretion, histamine is present in all tissues.
Many drugs used to treat neurologic and psychiatric Its concentration in the brain hypothalamus varies in
conditions act by altering the metabolism of these accordance with a circadian rhythm.
neurotransmitters. Histidine compounds present in the human body include:
Carnosine

L- -AMINO ACIDS
Alanine
Alanine serves as a carrier of ammonia and of the carbons of
pyruvate from skeletal muscle to liver via the Cori cycle, and
together with glycine constitutes a major fraction of the free
amino acids in plasma.
Arginine
Figure 301 summarizes the metabolic fates of arginine.
In addition to serving as a carrier of nitrogen atoms in urea
biosynthesis, the guanidino group of arginine is incorporated
into creatine, and following conversion to ornithine, its carbon
skeleton becomes that of the polyamines putrescine and
spermine.
The reaction catalyzed by NO synthase: (Figure 302)
a five-electron oxidoreductase with multiple cofactors
converts one nitrogen of the guanidine group of arginine
to L-ornithine and NO, an intercellular signaling molecule
that serves as a neurotransmitter, smooth muscle
relaxant, and vasodilator
Cysteine
Cysteine participates in the biosynthesis of coenzyme A by
reacting with pantothenate to form 4-phosphopantothenoyl-
cysteine.
dietarily derived ergothioneine and anserine
While their precise physiological functions are unknown,
carnosine (-alanyl-histidine) and homocarnosine (-
aminobutyrylhistidine) are major constituents of excitable
tissues, brain, and skeletal muscle.
Urinary levels of 3-methylhistidine are unusually low in
patients with Wilson disease.
Methionine
The major nonprotein fate of methionine is conversion to S-
adenosylmethionine, the principal source of methyl groups in
the body.
Biosynthesis of S-adenosylmethionine from methionine and
ATP is catalyzed by:
Methionine adenosyltransferase (MAT)
Human tissues contain three MAT isozymes:
MAT-1 and MAT-3 of liver
MAT-2 of nonhepatic tissues
Although hypermethioninemia can result from severely
decreased hepatic MAT-1 and MAT-3 activity, if there is
residual MAT-1 or MAT-3 activity and MAT-2 activity is
normal, a high tissue concentration of methionine will ensure
synthesis of adequate amounts of S-adenosylmethionine.
Following decarboxylation of S-adenosylmethionine by
methionine decarboxylase, three carbons and the -amino
group of methionine contribute to the biosynthesis of the
polyamines spermine and spermidine.
These polyamines function in cell proliferation and growth, are
growth factors for cultured mammalian cells, and stabilize
intact cells, subcellular organelles, and membranes.
Pharmacologic doses of polyamines are hypothermic and
hypotensive.
Since they bear multiple positive charges, polyamines readily
associate with DNA and RNA.

Serine
Serine participates in the biosynthesis of:
Sphingosine
purines and pyrimidines
where it provides carbons 2 and 8 of purines and the
methyl group of thymine
Genetic defects in cystathionine -synthase,
Serine + Homocysteine Cystathionine + H2O
a heme protein that catalyzes the pyridoxal 5-
phosphatedependent condensation of serine with
homocysteine to form cystathionine, result in homocystinuria
Tryptophan
Following hydroxylation of tryptophan to
hydroxytryptophan by liver tryptophan hydroxylase,
subsequent decarboxylation forms serotonin
hydroxytryptamine)a potent vasoconstrictor and stimulator
of smooth muscle contraction.
Catabolism of serotonin is initiated by:
deamination to 5-hydroxyindole-3-acetate, a reaction
catalyzed by monoamine oxidase
The psychic stimulation that follows administration of
iproniazid results from its ability to prolong the action of
serotonin by inhibiting monoamine oxidase.
In carcinoid (argentaffinoma):
tumor cells overproduce serotonin
Urinary metabolites of serotonin in patients with carcinoid
include:
N-acetylserotonin glucuronide
glycine conjugate of 5-hydroxyindoleacetate
Serotonin and 5-methoxytryptamine are metabolized to the
corresponding acids by monoamine oxidase.
N-Acetylation of serotonin, followed by its O-methylation in
the pineal body, forms melatonin.
Circulating melatonin is taken up by all tissues, including brain,
but is rapidly metabolized by hydroxylation followed by
conjugation with sulfate or with glucuronic acid.
Kidney tissue, liver tissue, and fecal bacteria all convert
tryptophan to tryptamine, then to indole 3-acetate.
The principal normal urinary catabolites of tryptophan are:
5-hydroxyindoleacetate
indole 3-acetate
Tyrosine
Neural cells convert tyrosine to epinephrine and
norepinephrine
While dopa is also an intermediate in the formation of melanin,
different enzymes hydroxylate tyrosine in melanocytes.
DOPA DECARBOXYLASE
A pyridoxal phosphate-dependent enzyme, forms
dopamine.
Subsequent hydroxylation, catalyzed by dopamine -oxidase,
then forms norepinephrine.
In the adrenal medulla:
phenylethanolamine-N-methyltransferase utilizes S-
adenosylmethionine to methylate the primary amine of
norepinephrine, forming epinephrine
Tyrosine is also a precursor of triiodothyronine and thyroxine.
Phosphoserine, Phosphothreonine, & Phosphotyrosine
The phosphorylation and dephosphorylation of specific seryl,
threonyl, or tyrosyl residues of proteins:
regulate the activity of certain enzymes of lipid and
carbohydrate metabolism and of proteins that
participate in signal transduction cascades
Sarcosine (N-Methylglycine)
The biosynthesis and catabolism of sarcosine ( N-
methylglycine) occur in mitochondria.
Formation of sarcosine from dimethyl glycine is catalyzed by:
the flavoprotein dimethyl glycine dehydrogenase which
requires reduced pteroylpentaglutamate (TPG)
Dimethylglycine + FADH2 + H4TPG + H2O Sarcosine
+ N-formyl-TPG
Traces of sarcosine can also arise by:
methylation of glycinea reaction catalyzed by glycine
N-methyltransferase
Glycine + S-Adenosylmethionine Sarcosine +
S-Adenosylhomocysteine
Catabolism of sarcosine to glycine, catalyzed by the
5- flavoprotein sarcosine dehydrogenase, also requires reduced
pteroylpentaglutamate.
(5-
Sarcosine + FAD + H4TPG + H2O Glycine + FADH2
+ N-formyl-TPG
The demethylation reactions that form and degrade sarcosine
represent important sources of one-carbon units.
FADH2 is reoxidized via the electron transport chain.
Creatine & Creatinine
Creatinine is formed in muscle from creatine phosphate by
irreversible, nonenzymatic dehydration, and loss of phosphate.
Since the 24-hour urinary excretion of creatinine is
proportionate to muscle mass, it provides a measure of
whether a complete 24-hour urine specimen has been
collected.
Glycine, arginine, and methionine all participate in creatine
biosynthesis.
Synthesis of creatine is completed by:
methylation of guanidoacetate by S-adenosylmethionine
NON- -AMINO ACIDS
Non--amino acids present in tissues in a free form include:
-alanine
-aminoisobutyrate
-aminobutyrate (GABA)
-Alanine is also present in:
combined form in coenzyme A
-alanyl dipeptides carnosine
anserine
homocarnosine
-Alanine & -Aminoisobutyrate
-Alanine and -aminoisobutyrate are formed during:
catabolism of the pyrimidines uracil and thymine,
respectively
Traces of -alanine also result from the hydrolysis of:
-alanyl dipeptides by the enzyme carnosinase
-Aminoisobutyrate also arises by:
transamination of methylmalonate semialdehyde, a
catabolite of l-valine
The initial reaction of -alanine catabolism is transamination
to malonate semialdehyde.
Subsequent transfer of coenzyme A from succinyl-CoA forms:
malonyl-CoA semialdehyde, which is then oxidized to
malonyl-CoA and decarboxylated to the amphibolic
intermediate acetyl- CoA
Analogous reactions characterize the catabolism of -
aminoisobutyrate.
 Transamination forms methylmalonate semialdehyde, which is
converted to the amphibolic intermediate succinyl-CoA by
reactions 8V and 9V.
Disorders of -alanine and -aminoisobutyrate metabolism
arise from defects in enzymes of the pyrimidine catabolic
pathway.
Principal among these are disorders that result from a total
or partial deficiency of dihydropyrimidine dehydrogenase.
-Alanyl Dipeptides
The -alanyl dipeptides carnosine and anserine ( N-
methylcarnosine) activate myosin ATPase, chelate copper, and
enhance copper uptake.
-Alanylimidazole buffers the pH of anaerobically contracting
skeletal muscle.
Biosynthesis of carnosine is catalyzed by:
carnosine synthase in a two-stage reaction that involves
initial formation of an enzyme-bound acyl-adenylate of -
alanine and subsequent transfer of the -alanyl moiety to
l-histidine
ATP + -Alanine -Alanyl-AMP + PPi
-Alanyl-AMP + l-Histidine Carnosine + AMP
Hydrolysis of carnosine to -alanine and l-histidine is
catalyzed by carnosinase.
The heritable disorder carnosinase deficiency is
characterized by carnosinuria.
Homocarnosine
present in human brain at higher levels than carnosine
synthesized in brain tissue by carnosine synthase
Serum carnosinase does not hydrolyze homocarnosine.
Homocarnosinosis
a rare genetic disorder, is associated with progressive
spastic paraplegia and mental retardation
-Aminobutyrate
-Aminobutyrate (GABA)
functions in brain tissue as an inhibitory
neurotransmitter by altering transmembrane potential
differences
is formed by decarboxylation of glutamate by l-glutamate
decarboxylase
Transamination of -aminobutyrate forms succinate
semialdehyde, which can be reduced to -hydroxybutyrate by
l-lactate dehydrogenase, or be oxidized to succinate and
thence via the citric acid cycle to CO2 and H2O.
A rare genetic disorder of GABA metabolism involves a
defective GABA aminotransferase, an enzyme that
participates in the catabolism of GABA subsequent to its
postsynaptic release in brain tissue.
Defects in succinic semialdehyde dehydrogenase, are
responsible for 4-hydroxybutyric aciduria a rare metabolic
disorder of -aminobutyrate catabolism characterized by the
presence of 4-hydroxybutyrate in urine, plasma and
cerebrospinal fluid.
No present treatment is available for the accompanying mild
to severe neurologic symptoms.
SUMMARY
In addition to serving structural and functional roles in
proteins, -amino acids participate in a wide variety of other
biosynthetic processes.
Arginine provides the formamidine group of creatine and the
nitrogen of NO. Via ornithine, arginine provides the skeleton
of the polyamines putrescine, spermine, and spermidine.
Cysteine provides the thioethanolamine portion of coenzyme
A, and following its conversion to taurine, is part of the bile
acid taurocholic acid.
Glycine participates in the biosynthesis of heme, purines,
creatine, and N-methylglycine (sarcosine). Many drugs and
drug metabolites are excreted as glycine conjugates, which
increases water solubility for urinary excretion.
Decarboxylation of histidine forms the neurotransmitter
histamine. Histidine compounds present in the human body
include ergothioneine, carnosine, and anserine.
S-Adenosylmethionine, the principal source of methyl groups
in metabolism, contributes its carbon skeleton to the
biosynthesis of the polyamines spermine and spermidine.
In addition to its roles in phospholipid and sphingosine
biosynthesis, serine provides carbons 2 and 8 of purines and
the methyl group of thymine.
Key tryptophan metabolites include serotonin and melatonin.
Kidney and liver tissue, and also fecal bacteria, convert
tryptophan to tryptamine and thence to indole 3-acetate, The
principal tryptophan catabolites in urine are indole 3-acetate
and 5-hydroxyindoleacetate.
Tyrosine forms norepinephrine and epinephrine, and following
iodination the thyroid hormones triiodothyronine and
thyroxine.
The enzyme-catalyzed interconversion of the phospho- and
dephospho-forms of peptide bound serine, threonine, and
tyrosine plays key roles in metabolic regulation, including
signal transduction.
Glycine, arginine, and S-adenosylmethionine all participate in
the biosynthesis of creatine, which as creatine phosphate
serves as a major energy reserve in muscle and brain tissue.
Excretion in the urine of its catabolite creatinine is
proportionate to muscle mass.
-Alanine and -aminoisobutyrate both are present in tissues
as free amino acids. -Alanine also occurs in bound form in
coenzyme A, carnosine, anserine, and homocarnosine.
Catabolism of -alanine involves stepwise conversion to acetyl-
CoA. Analogous reactions catabolize -aminoisobutyrate to
succinyl-CoA. Disorders of -alanine and -aminoisobutyrate
metabolism arise from defects in enzymes of pyrimidine
catabolism.
Decarboxylation of glutamate forms the inhibitory
neurotransmitter -aminobutyrate (GABA). Two rare
metabolic disorders are associated with defects in GABA
catabolism.