Alanine serves as a carrier of ammonia and of the carbons of pyruvate from skeletal muscle to liver via the Cori cycle (see Chapter 19), and together with glycine constitutes a major fraction of the free amino acids in plasma.
Figure 30–1 summarizes the metabolic fates of arginine. In addition to serving as a carrier of nitrogen atoms in urea biosynthesis (see Figure 28–16), 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 (see below).
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.
The reaction catalyzed by NO synthase, EC 126.96.36.199 (Figure 30–2), 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 (see Chapter 51).
The reaction catalyzed by nitric oxide synthase.
Cysteine participates in the biosynthesis of coenzyme A (see Chapter 44) by reacting with pantothenate to form 4-phosphopantothenoyl-cysteine (Figure 30–3). Three enzyme-catalyzed reactions convert cysteine to taurine, which can displace the coenzyme A moiety of cholyl-CoA to form the bile acid taurocholic acid (see Chapter 26). The conversion of cysteine to taurine is initiated by its oxidation to sulfinoalanine (cysteine sulfinate), catalyzed by the nonheme Fe2+ enzyme cysteine dioxygenase, EC 188.8.131.52. Decarboxylation of cysteine sulfinate by sulfinoalanine decarboxylase, EC 184.108.40.206 forms hypotaurine, whose oxidation by hypotaurine dehydrogenase (EC 220.127.116.11) forms taurine (Figure 30–4).
The reaction catalyzed by phosphopanto-thenate cysteine ligase (EC 18.104.22.168).
Conversion of cysteine to taurine. The reactions are catalyzed by cysteine dioxygenase, cysteine sulfinate decarboxylase, and hypotaurine decarboxylase, respectively.
Many metabolites and pharmaceuticals are excreted as water-soluble glycine conjugates. Examples include glycocholic acid (see Chapter 26) and hippuric acid formed from the food additive benzoate (Figure 30–5). Many drugs, drug metabolites, and other compounds with carboxyl groups are conjugated with glycine, which makes them more water-soluble and thereby facilitates their excretion in the urine. Glycine is incorporated into creatine, and the nitrogen and α-carbon of glycine are incorporated into the pyrrole rings and the methylene bridge carbons of heme (see Chapter 31), and the entire glycine molecule becomes atoms 4, 5, and 7 of the purines (see Figure 33–1).
Biosynthesis of hippurate. Analogous reactions occur with many acidic drugs and catabolites.
Decarboxylation of histidine to histamine is catalyzed by the pyridoxal 5′-phosphate-dependent enzyme histidine decarboxylase, EC 22.214.171.124 (Figure 30–6). A biogenic amine that functions in allergic reactions and gastric secretion, histamine is present in all tissues. Its concentration in the brain hypothalamus varies in accordance with a circadian rhythm. Histidine compounds present in the human body include carnosine, and dietarily derived ergothioneine and anserine (Figure 30–7). While their precise physiological functions are unknown, carnosine (β-alanyl-histidine) and homocarnosine (γ-aminobutyryl-histidine) are major constituents of excitable tissues, brain, and skeletal muscle. Urinary levels of 3-methylhistidine are unusually low in patients with Wilson disease.
The reaction catalyzed by histidine decarboxylase.
Derivatives of histidine. Colored boxes surround the components not derived from histidine. The SH group of ergothioneine derives from cysteine.
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), EC 126.96.36.199 (Figure 30–8). Human tissues contain three MAT isozymes: MAT-1 and MAT-3 of liver and 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.
Biosynthesis of S-adenosylmethionine, catalyzed by methionine adenosyltransferase.
Following decarboxylation of S-adenosylmethionine by methionine decarboxylase (EC 188.8.131.52), three carbons and the α-amino group of methionine contribute to the biosynthesis of the polyamines spermine and spermidine (Figure 30–9). 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. Figure 30–9 summarizes the biosynthesis of polyamines from methionine and ornithine, and Figure 30–10 the catabolism of polyamines.
Intermediates and enzymes that participate in the biosynthesis of spermidine and spermine.
Catabolism of polyamines.
Serine participates in the biosynthesis of sphingosine (see Chapter 24), and of purines and pyrimidines, where it provides carbons 2 and 8 of purines and the methyl group of thymine (see Chapter 33). Genetic defects in cystathionine β-synthase, EC 184.108.40.206
Serine + Homocysteine → Cystathionine + H2O
a heme protein that catalyzes the pyridoxal 5′-phosphate-dependent condensation of serine with homocysteine to form cystathionine, result in homocystinuria.
Following hydroxylation of tryptophan to 5-hydroxytryptophan by liver tryptophan hydroxylase (EC 220.127.116.11), subsequent decarboxylation forms serotonin (5-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, EC 18.104.22.168 (Figure 30–11). 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 and the 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 and indole 3-acetate.
Biosynthesis and metabolism of serotonin and melatonin. ([NH4+], by transamination; MAO, monoamine oxidase; ~CH3, from S-adenosylmethionine.)
Neural cells convert tyrosine to epinephrine and norepinephrine (Figure 30–12). While dopa is also an intermediate in the formation of melanin, different enzymes hydroxylate tyrosine in melanocytes. Dopa decarboxylase EC 22.214.171.124, a pyridoxal phosphate-dependent enzyme, forms dopamine. Subsequent hydroxylation, catalyzed by dopamine β-oxidase (EC 126.96.36.199), then forms norepinephrine. In the adrenal medulla, phenylethanolamine-N-methyltransferase (EC 188.8.131.52) utilizes S-adenosylmethionine to methylate the primary amine of norepinephrine, forming epinephrine (Figure 30–12). Tyrosine is also a precursor of triiodothyronine and thyroxine (see Chapter 41).
Conversion of tyrosine to epinephrine and norepinephrine in neuronal and adrenal cells. (PLP, pyridoxal phosphate.)
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 (see Chapters 9, Figures 18–20 and 22-26), and of proteins that participate in signal transduction cascades (see Chapter 42).
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 EC 184.108.40.206, which requires reduced pteroylpentaglutamate (TPG).
Dimethylglycine + FADH2 + H4TPG + H2O → Sarcosine + N-formyl-TPG
Traces of sarcosine can also arise by methylation of glycine, a reaction catalyzed by glycine N-methyltransferase, EC 220.127.116.11.
Glycine + S-Adenosylmethionine → Sarcosine + S-Adenosylhomocysteine
Catabolism of sarcosine to glycine, catalyzed by the flavoprotein sarcosine dehydrogenase EC 18.104.22.168, also requires reduced pteroylpentaglutamate.
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 (see Chapter 13).
Creatinine is formed in muscle from creatine phosphate by irreversible, nonenzymatic dehydration, and loss of phosphate (Figure 30–13). 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 (Figure 30–13).
Biosynthesis of creatine and creatinine. Conversion of glycine and the guanidine group of arginine to creatine and creatine phosphate. Also shown is the nonenzymic hydrolysis of creatine phosphate to creatinine.