Function

Typically, PLP forms a Schifl'base with the «-amino group of a lysine residue, which is then stabilized further by other neighboring residues. B6-dependent enzymes facilitate transaminations, decarboxylations, and other reactions.

Carbohydrate metabolism: There are at least three distinct glycogen phosphorylascs (EC2.4.L1) with tissue-specific expression (liver, muscle, and brain types) thai require lysine-bound PLP as a cofactor tor the mobilization of glucose from glycogen. Glucosamine-fructosc-6-phosphate aminotransferase (EC2.6.1.16. PLP-depend-cnt) is the rate-limiting enzyme for the synthesis of hexosamine and thus important for the N- and O-glycosylation of proteins.

Heme synthesis Delta-ami no levulinatc synthase (EC2.3.1.37) catalyzes the initial step of porphyrin synthesis, the condensation of succinyl-CoA and glycine to

Enzyme Pyndonal 5 -phosphate

Enzyme Pyndonal 5 -phosphate

Figur» 10.27 Pyndoxal-5'-phosphate forms a Schiff base with a specific lysyl r-äniino group in enzymes delta-ami nolcvulinic acid. Since the oxygen-transport system and numerous enzymes use porphyrin-derived cofactors or prosthetic groups (including heme, myoglobin, and cytochromes), this reaction is crucial for all tissues.

Neurotransmitter synthesis: PLP is a known or presumed component of several enzymes involved m the synthesis and catabolism of compounds that affect brain function, including glutamate, GABA, serotonin, catecholamines, histamine, tryptamine, taurine. D-senne. N-methy I - D-aspartatc. glycine, proline. Tryptamine. dopamine and serotonin are produced by DOPA decarboxylase (EC4.I.L28), histamine by histidine decarboxylase (EC4.1.1.22), and L-DOPA by tyrosine phenol-lyase (no EC#).Gamma-aminobutyrate (GABA) is synthesized by glutamate decarboxylase (EC'4.1.1.15) and inactivated by 4-aminobutyrate aminotransferase (EC'2.6.1,19). Suliiuoalanine decarboxylase (EC4.I.1.29) catalyzes the initial step of taurine synthesis.

D-a$partatc for N-methy 1-D-aspartate synthesis is generated by aspartate raccmase (no EC number assigned) and D-scrinc is produced by serine raccmase (no EC number assigned!. These compounds are endogenous ligands of the N-mclhyl-D-asparlate receptor (Wolosker et«/.. 1999).

Urea cycle; A PLP-containing enzyme of the mitochondrial matrix (ornithine-oxo-acid aminotransferase; EC2.6.1.13) is needed for the second step of urea synthesis Amino acid synthesis and catabolism: The vast majority of all known Bb-dependent enzymes move amino groups to or from amino acids and their precursors. The only amino acid that does not rely exclusively on at least one such reaction is proline Additional PLP-depcndent enzymes acting on amino acids include decarboxylases (such as ornithine decarboxylase; EC4.1.1.17), a raccmase (serine racemase. no EC number assigned), aldolases (threonine aldolase; EC4.I.2.5). and dehydratases (e.g. threonine dehydratase; EC 4.2.1.16).

Clycine: Enzymes contributing to glycine synthesis include 2-amino-3-ketobutvrate coenzyme A ligase (EC2.3.1.29), alanine-glyoxylate aminotransferase (EC'2.6.1.44), glycine hydroxymethy¡transferase (EC2.1.2.1) and. to a much lesser extent, kynureninc-glyoxylate aminotransferase (EC2.6.1 63). and aroniatic-amino-acid-glyoxylate aminotransferase (EC2.6.1.60). A catabolie enzyme is the P protein of the glycine cleavage complex (EC2.1,2.10).

L-Alanine: Alanine aminotransferase (ALT, EC2.6.I.2) is one of the major enzymes in muscle and liver.

Valine leucine isoleucm The breakdown of these three bulky amino acids is initiated by branched-chain amino acid aminotransferase (EC2.6.1.42). Valine transaminase (no EC number) may also be active in humans.

Proline: The only step involving a PLP-dependent enzyme is ornithine-oxo-acid aminotransferase (EC2.6.1.13, PLP-dependent), which participates in the synthesis of argtnine from proline in the gut.

Phenylalanine/tyrosine: Catabolie enzymes include phenylalanine(histidine) aminotransferase (EC2.6.1.5S), glutamine-pheny¡pyruvate aminotransferase (EC2.6.1.64), kynurenine-glyoxylate aminotransferase (EC2.6.1.63), aromattc-amino-acid-glyoxylate aminotransferase (EC'2.6.1,60), dihydroxyphenylalanine aminotransferase (EC2.6.L49). tyrosine aminotransferase (EC2.6.1.5), and aromatic-amtno-acid-glyoxylatc aminotransferase (EC2.6.L60).

Tryptophan: Several PLP-dependent enzymes participate in its metabolism, including tryptophan aminotransferase (EC2.6.1.27), kvnureninase (EC3.7.1.3), kynurenine-oxoglutarate aminotransferase (EC2.ii.1.7), kynurenine-glyoxylate aminotransferase (EC'2.6.1.63). and aromatic-amioo-acid-glyoxylate aminotransferase (EC2.6.1.60). Methionine/cysteine: The transsul filiation pathway uses the PLP-dependent enzymes cystathionine beta-synthase (EC4.2.1.22) and cystathionine-gamma-lyasc (EC4.4.1.1). The deamiflation of cysteine can then be catalyzed by cysteine aminotransferase (EC'2.6.1.3). An alternative transamination reaction for I.-methionine can be catalyzed by glutamine pyruvate aminotransferase (EC2.6.1,15), Serine: Conversion to and from glycine depends on glycine hydroxy met hyltransferase (EC2,1.2.1 >. Serine dehydratase (EC 4.2.1.13) and threonine dehydratase<EC4.2.1.16). both PLP-dependent enzymes, converted some serine directly to pyruvate.

Serine racemase (no EC number assigned) generates D-serine. an important neuromodulator in brain.

Threonine: The main cytosolic pathway of threonine degradation starts with PLP-containing threonine dehydratase (EC4.2.I.16). Cleavage into glycine and acetalde-hyde by the two PLP-containing cytosolic enzymes threonine aldolase (EC4.1.2.5) and glycine hydroxymcthy I transferase (EC2.1.2.1) is a minor catabolic pathway in cvtosol. The second step of threonine catabolism in mitochondria uses PLP-dependent 2-amino-3-kctobutyrate coenzyme A ligase (EC2.3.1 -29).

Glutamate.'glutaminc/aspartate/asparagine: Numerous PLP-dependent enzymes move amino groups to and from these pivotal amino acids, including aspartate aminotransferase (AST. EC2.6.1.1), alanine aminotransferase (ALT. EC2.6.I.2). 4-amino-butyrate aminotransferase (EC2.6.1.19). Another important PLP-dependent enzyme is the GABA-synthesizing gluiamatc decarboxylase (EC4.1.1.15), Hist/dine: Aromatic -am ino-acid-glyoxy late aminotransferase (EC2.6.1.60) catalyzes transamination of L-histidine.

Lysine: Its breakdown uses 2-aminoadipate aminotransferase (EC2.6.I.39). Ornithine decarboxylase (EC'4.1.1.17) catalyzes lysine conversion into cadaverine. Arginine: Both endogenous synthesis and catabolism rely on PLP-containing enzymes, most importantly ornithine-oxo-aeid aminotransferase (EC'2.6.1.13). Carnitine: The third step of carnitine synthesis is catalyzed by PLP-dependent serine hydroxymethyltransferase (EC2.1.2.1).

Taurine: The initial step of taurine synthesis depends on sulfinoalanine decarboxylase (EC4.1.1.29).

Lipid metabolism: B6 is also important for the synthesis and metabolism of various lipids. Sphingosinc, produced by PLP-containing serine C-palmitoyltransferase (EC2.3.1.50), is part of myelin, eeramides and sphingolipids in brain, nerves and other tissues. For still unclear reasons B6 in some form is also needed for full activity of 6-desaturase (EC 1.14.99,25), which extends the chain length of omega-3 delta fatty acids Reduced activity impairs the production of EPA and DHA from dietary precursors, such as alpha-linolenic acid (Tsugc et ol„ 2000). Similarly. B6 deficiency greatly diminishes peroxisomal acyl-CoA oxidase (EC1.3.3.6) activity, which catalyzes the initial reaction of fatty acid beta-oxidation in peroxisomes (Tsuge etal., 2000).

Selenium metabolism: Selenocysteine lyase (EC4.4.1,16, PLP-dependent) catalyzes tlie decomposition of L-selenocysteine to L-alanine and elemental selenium, thereby providing selenium to selenophosphate synthetase in selenoprotein biosynthesis, L-seryl-tRNASet selenium transferase (EC2.9.1.1, PLP-dependent) uses selenophosphate to substitute the hydroxy! oxygen of serine with selenium. Hormone metabolism: Diiodotyrosine aminotransferase (EC2.6.1.24) and/or thyroid-hormone aminotransferase (EC2.6.i.26) eataboEize and thereby inactivate thyroid hormones.

Vitamin metabolism: Kynureninase (HC3.7,1.3. PLP-dependcnt), is the key enzyme for niacin synthesis from tryptophan.

Xenobiotic metabolism: Cysteine conjugate beta-lyase (EC4.4.1.13) cleaves cysteine conjugates in the kidney, releasing ammonia and pyruvate.

Metabolic regulation: The activity of several enzymes is inhibited when PLP firmly binds to the protein. Understanding the significance of such actions is very preliminary. Examples include the effects on succinic scmialdehyde dehydrogenase in brain (Choi et ul.. 2001) and on tyrosine phosphatase in many tissues (Zhou el ul.. 1999).

The binding to steroid hormone receptors may be similar in some ways, but the significance is poorly understood.

References

Uahn JH, Kwon OS. Joo MM. Ho Jang S. Park J. Hwang IK. Rang TC. Won MH, Vil Kwon H, Kwok F. Kim MB. Cho SW. Choi SY, lmmuiiohistocliemical studies of brain pyridoxine-5'-phosphate oxidase. Brain Res 2002:925:159 68 Black AL. Guirard BM. Snell LE. Increased muscle phosphorylasc in rats fed high levels of vitamin 86. J Nutr 1977:107:1962 8 Choi SY. Balm JH. Lee BR. Jeon SG. Jang JS. Kim CK. Jin LH. Kim KH. Park JS, Park J. Cho SW. Brain succinic semialdehyde dehydrogenase: identification of reactive lysyl residues labeled with pyridoxa 1-5'-phosphate. J Neurochem 2001:76:919 25 Food and Nutrition Board. Institute of Medicine. Dietary Reference Intakes for thiamin, riboflavin, niacin, vitamin B6. folate, vitamin B12. pantothenic acid, biotin, and choline. National Academic Press. Washington, DC. 1948, pp.150 95 Gregory JF 111. Nutritional properties and significance of vitamin glycosides. Annu Rei Nutr 1998; I 8:277 96

Johansson S, Lindstedl S, Register U. Wadstrom 1 . Studies on the labeled pyridoxine in man. Am J Clin Nutr 1966; 18:185-96 Lee HS. Moon BJ. Choi SY. Kwon OS. Human pyridoxal kinase: overcxpression and properties of the recombinant enzyme. Molecules Cells 2000:10:452 9 McMahon LG, Nakano II. Levy MD. Gregory JF 3rd. Cytosolic pyridoxine-beta-D-glucoside hydrolase from porcine jejunal mucosa. Purification, properties, and comparison with broad specificity beta-glucosidase. J Bi»l Chem 1997:272:32025-33 Mehansho II, Buss DD. Hamm MW, Henderson LM, Transpon and metabolism of pyridoxine in rat liver. Biochim Biophvs Acta 1980:631:112-23 Merrill AH Jr. Flenderson JM. Wang E, McDonald BW. Millikan WJ. Metabolism of vitamin B-6 by human liver. J Nutr 1984; 114:1664-74

Schenker S. Johnson RE, Mahuren JD, Henderson (il. Coburn SP. Human placental vitamin B6 (pyridoxal) transport: normal characteristics and effects of ethanol. Am ■! PhysioI1992:262: R966-74 Shane H. Vitamin B6 and blood. In Human Vitamin Bf> Requirements: Proceedings of a

Workshop. Washington, DC. National Academy of Sciences. 1978, pp.111 28 Tadern K, Arima M, Yoshino S. Yagi F. Kobayasht A. Conversion of pyridoxine Into 6-hydroxypyridoxine by food components, especially ascorbic acid. .1 Nutr Set Vitamino! 1986:32:267-77 I rumbo PR. Banks MA, Gregory JF III. Hydrolysis ofpyndoxine-5'-beta-D-g)ucoside by a hroad-speci(icily beta-glucosidase from mammalian tissues. Proc Soc Exp Bio! Med l990;l95;24O-6

Tsuge H. Ilona NT. Effects of vitamin 13-6 on (n-3) polyunsaturated fatty acid metabolism. ./ Nutr 2000:130:333S 334S Wolosker II. Sheth K.N. Takahashi M. Mothet JP. Brady RÜ Jr. Ferris CD. Snyder SH. Purification of serine raeemase: biosynthesis of the neuromodulator D-serine. Proc Nat! Acad Sei ISA 1999;96:721-5 Zhang ¿VI. McCormick DB. Uptake of N-(4'-pyridoxyl)amines and release of amines by renal cells: a model for transporter-enhanced delivery of bioactlvc compounds. Proc Nat! Acad Set USA 1991:88:10407-10 Zhou M. Van litten RL. Structural basis of the light binding of pyridoxal 5'-phosphate to a low molecular weight protein tyrosine phosphatase. Biochem 1999:38:2636 46

Understanding And Treating Autism

Understanding And Treating Autism

Whenever a doctor informs the parents that their child is suffering with Autism, the first & foremost question that is thrown over him is - How did it happen? How did my child get this disease? Well, there is no definite answer to what are the exact causes of Autism.

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