Metabolism

Synthesis: CoA synthesis uses pantothenate, cysteine, one adenylate, three phosphates and the energy of six high-energy phosphates from ATP. Significant amounts of pantothenate are generated from pantetheine through the action of pantetheine hydrolase (EC3.5.1.-) which is expressed in many tissues, Panthenol and panthcnal may also be converted to a limited extent into pantothenate by alcohol dehydrogenase (EC 1,1.1.1) and aldehyde dehydrogenase (EC 1.2.1.3).

The initial phosphorylation of pantothenate by pantothenate kinase (PANK, EC2.7.1.33) is the rate-limiting step of CoA synthesis. In addition to the enzyme present in most tissues, a brain-specilic form (PANK.2) has been identified (Zhou et ul.. 2001 >. Phosphopantothcnatc can then be linked to cysteine by phosphopan-tothenate-cysteine ligase (EC6.3.2.5) and decarboxylated by pantolhenoyleyslcine decarboxylase (EC4.1,1.36). An alternative pathway catalyzed by pantothenoyl-cysteine decarboxylase (EC4.M.30) and pantetheine kinase (EC2.7.1.34) exists in liver and possibly other tissues. Whether this is a salvage pathway for inappropriately dephosphorylatcd paiitothcnoy(cysteine or has another significance remains uncertain,

CoA synthesis is completed either in eytosol or in mitochondria by a Afunctional CoA synthase complex that comprises both pantetheine phosphate adenyly I transferase (EC2.7.7.3) and dephospho-CpA kinase (EC2.7.1.24) activities. Different genes encode the cytosolic and mitochondrial forms of the CoA synthase complex. Significant transport of both pantothenic 4'-phosphate and CoA l Tahiliani, 19911 into mitochondria occurs, Much more CoA is inside mitochondria than in eytosol (75 45% depending on tissue), both due to the direction of the normal electrochemical gradient and metabolic trapping as acyl-CoA.

ho-c-c-ch—c-n-c—c—cooh h, j,,, i h h hj h, CH3 OH 0 „ *

Pantothenate

Pantolhenate kinase

HO-P-O-C-C-CH—C-N-C—C—COOH ! i., i " H H.. Hs

4 -phosphopantothenate

Pantothenale-cysteme igase

Pantothenoyl cysteine

Pantothenoyl*

cysteine decarboxylase

A ■ Phosphopantothenoylcysteine

Pantetheine

COt*^ Pantetheine kinase i ATP + Mg Mg ADP

Phosphopanto-Ihenoylcyslaine decarboxylase

Pantetheine phosphate adenyfyl transferase

Oephospho CoA kinase

h, ç ? çhj c—o-p-o-p-o-c-c—ch—c-n-c-c-c-n-c-c-c-sh t i h2 i , i « h h; a h h; hj hj oh oh ' chjoh o - ?

Coenzyme A

Figur* 10.43 Pantothenate metabolism

Breakdown: CoA is hydrolyzed in multiple steps by as yet incompletely characterized phosphatases and pyrophosphatases. The final step is the hydrolysis of pantetheine to pantothenate and cystcamine by pantetheine hydrolase (EC3.5.L-). This enzyme circulates with blood is present in mucosal membranes, and is anchored to microsomal membranes.

Storage

Limited amounts of pantothenate are stored, especially in RBC and adipose tissue. Pantothenate is mobilized again by hydrolysis of pantetheine to pantothenate.

Excretion

Most pantothenate losses occur in the kidney. Pantothenate is the main form in urine.

Significant amounts of Co A and other pantothenate-re la led compounds are filtered in the kidney and hase to be recovered front the tubular lumen. Nucleotide pyrophosphatase (EC3.6.1.9) at the brush border of proximal tubular epithelium releases pantothenate from Co A (Byrd el a/., 19X51. Another brush border enzyme that generates transportable pantothenate is pantetheine hydrolase {EC3.5.1.-) in the proximal tubular epithelium. Transport of pantothenate across the tubular brush border membrane is driven by the inward sodium gradient (Barbara! and Podevin, 19X6). presumably via the sodium-dependent multivitamin carrier (SLC5A6). Little is known about how pantothenate crosses the basolateral membrane anil returns into circulation. Transport also occurs in the opposite direction, and pantothenate excess can be secreted into tubules (Kamitz eral.t 19X4).

Regulation

Protein kinase C- and calcium calmodulin regulate the activity of the sodium-dependent multivitamin carrier (SLC5A6).

Function

Numerous metabolic activities depend on adequate availability of pantothenate, only a few of which can be mentioned here. Most pantotbenate-dependent reactions use CoA as the near universal donor and acceptor of acetyl and acyl groups. CoA is thus indispensable for the metabolism of carbohydrates, fatty acids, ethanol. and ammo acid> (with the exception of a small proportion of glycine). The consequences of a lack of CoA synthesis in brain have become more apparent with the identification of a defective brain-specific form of pantetheine kinase 2 (PANK2) as the cause of Hallervorden Spat/ syndrome (Zhou et at., 20111). This severe neurodegenerative disorder with onset in childhood is characterized by increasing iron accumulation in the basal ganglia of the brain, and progressive extrapyramidal dysfunction. It is not known, however, which pantothenate-requiring processes are involved.

A few reactions use J'-phosphopanletheine, most of them are related to lipid synthesis. in alt these instances the substrates form a thiolester with CoA or 4'-phospho-pantetheine which can then be metabolized further. An example of an enzyme with 4'-phosphopantethcine as a prosthetic group is the (¡TP-dependent acyl-CoA synthetase (aeid-C'oA Iigase/GDP-forming; EC6.2.1.IG). This enzyme is distinct from other aeyl-CoA synthetases which are energized by ATP and do not contain phospho-pantcthcine. Effects or functions of other pantothenatc-related compounds or precursors. such as pantethine. are less certain.

Intermediary metabolism: The production of acetyl-C'oA from pyruvate and succinyl-CoA from alpha-ketoglutarate constantly consumes large amounts of CoA, The reactivation of the ketone bodies aeetoacetate and hydroxy but y rale also draws on the CoA pool of a cell. The same is true for other metabolites that feed into the Krebs cycle, such as acetate and ethanol.

Lipid metabolism: Katty acid synthesis starts from acetyi-CoA, cholesterol synthesis from hydroxymethyl glutaryl-CoA. Fatty acids also have to be linked to CoA before ¡hey can be metabolized via beta-oxidation. Fatty acids with an odd number of carbons. methionine, valine, threonine, and the side-chain of cholesterol can be metabolized only after ligation to CoA. Bile acids, which are essential for fat absorption, undergo C'oA-dependent conjugation to taurine or glycine before they are secreted into bile.

Protein acylation: During or after translation many proteins must be modified to become fully functional, and many of these modifications use CoA as a eofactor. Important types of modification are the acetylation of protein N-termini. acylation of proteins with acctate (e.g.. lysine ofalpha-tubulinc), myristate or palmitate. Xenobiotic detoxification: Conjugation of aromatic, heterocyclic or other complex compounds to glycine, taurine, or glucuronate typically requires an initial activation step. The metabolism of benzoate in the liver is a typical example. The free acid is lirst joined to COA by either of two mitochondrial xenobiotic'medium-chain fatty acid:CoA ligases (XM-ligases, Vessey et id., 1999). Glycine N-acy 1 transferase (EC2.3. 1.131 or glycine N-benzoyl transferase (F.C2.3.1.71) can then use glycine to transform the activated benzoate into hippuratc and release CoA again (Grcgus et id.. 1999). Acy I carrier protem: Holo-[acyl-carrier protein] synthase (EC2.7.8.7) uses CoA to attach a 4'-phosphopantctheine residue to the acyl carrier protein subunii of fatty acid synthase (EC2.3.1.85). The 4'-phosphopantctheine anchors the nascent fatty acid and pivots n to the active centers of other components of the fatty acid synthase complex.

A distinct form of the acyl carrier protein (NDUFABI) constitutes the 9.6kD subunit of NADH-ubiquinone oxidoreductase. a component of the respiratory complex I (Triepels et ul., 1999). The precise function of the acyl carrier protein in complex 1 is nol known, but a role in fatty acid and polypeptide synthesis has been suggested.

Other forms: I'antethine may enhance the anti-aggregation activity of the chape rone alpha-crystal I in (Clark and Huang, 19%). but the physiological significance of such an action needs further clarification.

References

An nous KE Song WO. Pantothenic acid uptake and metabolism by red blood cells of rats.

JNurr 1995;125:2886-93 Baker H, Erank O, Deangclis B. feingold S. Kaininet/ky HA. Role of placenta in maternal-

fetal vitamin transfer in humans. Am J Obstel Gynecol 1981;141:792-6 Barbara I B. Podevin RA. Pantothcnatc-sodium cotransport in renal brush border membranes. J Biol Chem 19X6:261:14455-60 Byril JC". Feamey FJ, Kim VS. Rat intestinal nucleotide-sugar pyrophosphatase. Localization, partial purification, and substrate specificity. J Biol Chem 1985^60:747+ NO Chatieijec \S, Kumar CK. Ortiz A, Rubin SA. Said HM. Molecular mechanism of the intestinal hiotin transport process. Am J Physiol 1999;277:C605 13

Clark JI. 11 Liang Ql Modulation of the chaperone-like acti\ ity of bovine alpha-crystal Iin.

Pmc Natl Acad Sci USA 1996;93:15185-9 Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for thiamin, riboflavin, niacin, vitamin 146. folate, vitamin B12, pantothenic acid biotin. and choline. National Academy Press. Washington, DC. 1998. pp.357- 73 Greens Z, llalaszi L. Klaassen CD. Effect of chlorophenoxyacetic acid hcrbicidcs un glycine conjugation of benzoic acid. Xenobiotica 1999:29:547 59 Karnitz LM, Gross CJ. Henderson LM Transport and metabolism of pantothenic acid by-

tat kidney. Biochim Biophys Acta 1984;769:486 92 Prasad PD. Srinivas SR. Wang H. Leibach FH, Dcvoe LD. Ganapathy V F.lectrogenic nature of rat sodium-dependent multivitamin transport. Biochem Biophys Res Comm 2000:270; 836-4(1

Prasad PD. Wang M. Kekuda R. Fujita T. Fei VJ, Devoe LD, Leibach FH, Ganapathy V. Cloning and functional expression of a cDNA encoding a mammalian sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin, and lipoate../ Biol Chem 1998:273:7501 -6 Saliha KJ, Homer HA, Kirk K. Transport and metabolism of the essential vitamin pantothenic acid in human erythrocytes infected with Ihe malaria parasite Plasmodium falciparum. J Biol Chem 1998;273:10190-5 Shibata K. Gross CJ. Henderson LM. Hydrolysis and absorption of pantothenate and its coenzymes in the rat small intestine. J Star 1983; 113:2107-15 Tahiliani AG. Evidence for nef uptake and efflux of mitochondrial coenzyme A. Biochim

Biophys Acta 199l;I067:29 37 Tahiliani AG, Beinlich CJ. Pantothenic acid in health and disease, litam Harm 1991;46:165-228

Triepels R. Smeitink J, Loeffen J. Smeets R. Buskcns C. Trijbels F, van den 1 leuv el I . The human nuclear-encoded acvl carrier subunit (NDUFABI} of the mitochondrial complex I in human pathology.,/ fnher Mctah Dis 1999:22; 163 73 Vessey DA. Kelley M. Warren RS. Characterization of the CoA ligases of human liver mitochondria catalyzing the activation of short- and medium-chain fatty acids and xenobiotic carboxylic acids, Biochim Biophys tcia 1999.1428:455-62 Zhou B, Westaway SK. Levinson B. Johnson MA. Gitschier .1. Hayflick S.I. A novel pantothenate kinase gene iPANK2i is defective in llallervorden-Spatz syndrome. Nature Cienet 2001:28:345 9

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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