Biomedical Importance

Important products derived from amino acids include heme, purines, pyrimidines, hormones, neurotransmitters, and biologically active peptides. In addition, many proteins contain amino acids that have been modified for a specific function such as binding calcium or as intermediates that serve to stabilize proteins—generally structural proteins—by subsequent covalent cross-linking. The amino acid residues in those proteins serve as precursors for these modified residues. Small peptides or peptide-like molecules not synthesized on ribosomes fulfill specific functions in cells. Histamine plays a central role in many allergic reactions. Neurotransmitters derived from amino acids include y-aminobutyrate, 5-hydroxytryptamine (serotonin), dopamine, norepinephrine, and epinephrine. Many drugs used to treat neurologic and psychiatric conditions affect the metabolism of these neurotransmitters.

Glycine

Metabolites and pharmaceuticals excreted as water-soluble glycine conjugates include glycocholic acid (Chapter 24) and hippuric acid formed from the food additive benzoate (Figure 31-1). Many drugs, drug metabolites, and other compounds with carboxyl groups are excreted in the urine as glycine conjugates. Glycine is incorporated into creatine (see Figure 31-6), the nitrogen and a-carbon of glycine are incorporated into the pyrrole rings and the methylene bridge carbons of heme (Chapter 32), and the entire glycine molecule becomes atoms 4, 5, and 7 of purines (Figure 34-1).

P-Alanine

P-Alanine, a metabolite of cysteine (Figure 34-9), is present in coenzyme A and as P-alanyl dipeptides, principally carnosine (see below). Mammalian tissues form P-alanine from cytosine (Figure 34-9), carnosine, and anserine (Figure 31-2). Mammalian tissues transami-nate P-alanine, forming malonate semialdehyde. Body fluid and tissue levels of P-alanine, taurine, and

P-aminoisobutyrate are elevated in the rare metabolic disorder hyperbeta-alaninemia.

P-Alanyl Dipeptides

The P-alanyl dipeptides carnosine and anserine (V-methylcarnosine) (Figure 31-2) activate myosin ATPase, chelate copper, and enhance copper uptake. P-Alanyl-imidazole buffers the pH of anaerobically contracting skeletal muscle. Biosynthesis of carnosine is catalyzed by carnosine synthetase in a two-stage reaction that involves initial formation of an enzyme-bound acyl-adenylate of P-alanine and subsequent transfer of the P-alanyl moiety to L-histidine.

ATP + P -Alanine ^P -Alanyl - AMP ^+PP| P-Alanyl - AMP + L-Histidine ^ Carnosine + AMP

Hydrolysis of carnosine to P-alanine and L-histidine is catalyzed by carnosinase. The heritable disorder carnosinase deficiency is characterized by carnosinuria.

Homocarnosine (Figure 31-2), present in human brain at higher levels than carnosine, is synthesized in brain tissue by carnosine synthetase. Serum carnosinase does not hydrolyze homocarnosine. Homocarnosinosis, a rare genetic disorder, is associated with progressive spastic paraplegia and mental retardation.

Phosphorylated Serine, Threonine, & Tyrosine

The phosphorylation and dephosphorylation of seryl, threonyl, and tyrosyl residues regulate the activity of certain enzymes of lipid and carbohydrate metabolism and the properties of proteins that participate in signal transduction cascades.

Methionine

S-Adenosylmethionine, the principal source of methyl groups in the body, also contributes its carbon skeleton for the biosynthesis of the 3-diaminopropane portions of the polyamines spermine and spermidine (Figure 31-4).

Benzoate

Benzoate

CoASH

Benzoyl-CoA

Glycine

CoASH

Hippurate

Figure 31-1. Biosynthesis of hippurate. Analogous reactions occur with many acidic drugs and catabolites.

Cysteine

L-Cysteine is a precursor of the thioethanolamine portion of coenzyme A and of the taurine that conjugates with bile acids such as taurocholic acid (Chapter 26).

Histidine

Decarboxylation of histidine to histamine is catalyzed by a broad-specificity aromatic L-amino acid decarboxylase that also catalyzes the decarboxylation of dopa, 5-hy-droxytryptophan, phenylalanine, tyrosine, and tryptophan. a-Methyl amino acids, which inhibit decarboxylase activity, find application as antihypertensive agents. Histidine compounds present in the human body include ergothioneine, carnosine, and dietary anserine (Figure 31-2). Urinary levels of 3-methylhistidine are unusually low in patients with Wilson's disease.

Ornithine & Arginine

Arginine is the formamidine donor for creatine synthesis (Figure 31-6) and via ornithine to putrescine, sper-mine, and spermidine (Figure 31-3) Arginine is also the precursor of the intercellular signaling molecule ni-

Ergothioneine

Carnosine

O CH2

Anserine

CH2 C

Homocarnosine

Figure 31-2. Compounds related to histidine. The boxes surround the components not derived from histidine. The SH group of ergothioneine derives from cys-teine.

tric oxide (NO) that serves as a neurotransmitter, smooth muscle relaxant, and vasodilator. Synthesis of NO, catalyzed by NO synthase, involves the NADPH-dependent reaction of L-arginine with O2 to yield L-cit-rulline and NO.

Polyamines

The polyamines spermidine and spermine (Figure 31-4) 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

Glutamate-y-semialdehyde

Glutamate-y-semialdehyde

PROTEINS

PROLINE

GLUTAMATE

Figure 31-3. Arginine, ornithine, and proline metabolism. Reactions with solid arrows all occur in mammalian tissues. Putrescine and spermine synthesis occurs in both mammals and bacteria. Arginine phosphate of invertebrate muscle functions as a phosphagen analogous to creatine phosphate of mammalian muscle (see Figure 31-6).

and hypotensive. Since they bear multiple positive charges, polyamines associate readily with DNA and RNA. Figure 31-4 summarizes polyamine biosynthesis.

Tryptophan

Following hydroxylation of tryptophan to 5-hydroxy-tryptophan by liver tyrosine hydroxylase, subsequent decarboxylation forms serotonin (5-hydroxytrypta-

mine), a potent vasoconstrictor and stimulator of smooth muscle contraction. Catabolism of serotonin is initiated by monoamine oxidase-catalyzed oxidative deamination to 5-hydroxyindoleacetate. 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 carci-

Decarboxylated s-adenosylmethionine '

Methylthio-, adenosine

Spermidine

SPERMINE SYNTHASE

Spermine

Figure 31-4. Conversion of spermidine to spermine. Spermidine formed from putrescine (decarboxylated L-ornithine) by transfer of a propylamine moiety from decarboxylated S-adenosylmethionine accepts a second propylamine moiety to form spermidine.

+H3N

NH3+

NH3+

TYROSINE HYDROXYLASE

NH3+

L-Tyrosine

TYROSINE HYDROXYLASE

NH3+

CH2 Dopa

CH2 Dopa

DOPA DECARBOXYLASE

PLP k

DOPAMINE ß-OXIDASE

Dopamine

O2 Cu2+

Vitamin C

DOPAMINE ß-OXIDASE

PHENYLETHANOL-AMINE N-METHYL-TRANSFERASE

Norepinephrine

S-Adenosylmethionine

S-Adenosylhomocysteine

CH N

Epinephrine

Figure 31-5. Conversion of tyrosine to epinephrine and norepinephrine in neuronal and adrenal cells. (PLP, pyridoxal phosphate.)

noid include A-acetylserotonin glucuronide and the glycine conjugate of 5-hydroxyindoleacetate. Serotonin and 5-methoxytryptamine are metabolized to the corresponding acids by monoamine oxidase. A-Acetylation of serotonin, followed by 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 and indole 3-acetate.

Tyrosine

Neural cells convert tyrosine to epinephrine and norepinephrine (Figure 31-5). While dopa is also an intermediate in the formation of melanin, different enzymes hydroxylate tyrosine in melanocytes. Dopa decarboxy-lase, a pyridoxal phosphate-dependent enzyme, forms dopamine. Subsequent hydroxylation by dopamine P-oxidase then forms norepinephrine. In the adrenal medulla, phenylethanolamine-A-methyltransferase utilizes S-adenosylmethionine to methylate the primary amine of norepinephrine, forming epinephrine (Figure 31-5). Tyrosine is also a precursor of triiodothyronine and thyroxine (Chapter 42).

Creatinine

Creatinine is formed in muscle from creatine phosphate by irreversible, nonenzymatic dehydration and loss of phosphate (Figure 31-6). The 24-hour urinary excretion of creatinine is proportionate to muscle mass. Glycine, arginine, and methionine all participate in creatine biosynthesis. Synthesis of creatine is completed by methylation of guanidoacetate by S-adenosylmethio-nine (Figure 31-6).

7-Aminobutyrate y-Aminobutyrate (GABA) functions in brain tissue as an inhibitory neurotransmitter by altering transmembrane potential differences. It is formed by decarboxyla-tion of L-glutamate, a reaction catalyzed by L-glutamate decarboxylase (Figure 31-7). Transamination of y-aminobutyrate forms succinate semialdehyde (Figure 31-7), which may then undergo reduction to y-hydroxy-butyrate, a reaction catalyzed by L-lactate dehydro-genase, or oxidation to succinate and thence via the citric acid cycle to CO2 and H2O. A rare genetic disorder of GABA metabolism involves a defective GABA amino-transferase, an enzyme that participates in the catabo-lism of GABA subsequent to its postsynaptic release in brain tissue.

h2n=c h2n=c

ch2 I

CH2 I

COO-L-Arginine

N-CH

CH3 Creatinine

(Kidney)

ARGININE-GLYCINE TRANSAMIDINASE

NONENZYMATIC IN MUSCLE

Ornithine

Glycocyamine (guanidoacetate)

(Liver)

S-Adenosyl-methionine

S-Adenosyl-homocysteine

GUANIDOACETATE METHYLTRANSFERASE

Creatine phosphate

Figure 31-6. Biosynthesis and metabolism of creatine and creatinine.

a-KA

Figure 31-6. Biosynthesis and metabolism of creatine and creatinine.

a-KA

+H3N — CH2 — CH2 — CH2 — COO-y-Aminobutyrate

COO-

y-Hydroxybutyrate

NAD+

COO-

a-Ketoglutarate

COO-

a-Ketoglutarate

CH2 I

COO-

Succinate semialdehyde

COO-

COO-

Succinate

Figure 31-7. Metabolism of y-aminobutyrate. (a-KA, a-keto acids; a-AA, a-amino acids; PLP, pyri-doxal phosphate.)

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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