P-pantetheine

CoA plays an important role in various metabolic reactions. This compound is used widely in biochemistry, and its usefulness in medicine and in analytical fields has been discussed. The recent discovery of an acyl carrier protein containing an intermediate of CoA biosynthesis, P-pantetheine, as a prosthetic group, has emphasized the significance of CoA and its derivatives in biochemistry. The biosynthesis of this coenz3mie from pantothenic acid, cysteine and ATP requires five sequential enz3miatic steps as follows (3)5... 

CoA, coenzyme A dephospho-CoA, 3 -dephospho-coenzyme A P-pantothenic acid, 4 -phosphopantothenic acid P-pantothenoyl-cysteine, 4 -phosphopantothenoylcysteine P-pantetheine, 4 -phos-phopantethelne ATP, adenosine 5 -triphosphate ADP, adenosine 5 -dlphosphate AMP, 5 -adenyllc acid CTP, cytidine 5 -triphosphate CMP, 5 -cytldylic acid GTP, guanosine 5 -triphosphate GMP, 5 -guanylic acid ITP, inosine 5 -triphosphate UTP, uridine 5 -tri-phosphate PPl, inorganic pyrophosphate. 

Keefe et al. (1995) from Stanley Miller s laboratory reported a possible prebiotic synthesis of pantetheine, the part of the CoA molecule without its ADP moiety. They were able to synthesize the CoA precursor from P-alanine, pantoyllactone and cysteamine. This condensation requires concentration of the reaction mixture the warm lagoon theory is required here in order to achieve prebiotic conditions ... 

Each reaction of p oxidation is catalyzed by a different enzyme. Chemically, they re pretty much the same as the reverse of the individual reaction of fatty acid synthesis, with two exceptions (1) p oxidation uses FAD for the formation of the double bond at the C-2 position, and (2) the reactions occur with the fatty acid attached to CoA rather than to the pantetheine of a multienzyme complex. 

Several amino acids are broken down by de-carbo qflation. This reaction gives rise to what are known as biogenic amines, which have various functions. Some of them are components of biomolecules, such as ethanolamine in phospholipids (see p. 50). Cysteamine and T-alanine are components of coenzyme A (see p.l2) and of pantetheine (see pp. 108, 168). Other amines function as signaling substances. An important neurotransmitter derived from glutamate is y-aminobutyrate (GABA, see p.356). The transmitter dopamine is also a precursor for the catecholamines epinephrine and norepinephrine (see p.352). The biogenic amine serotonin, a substance that has many effects, is synthesized from tryptophan via the intermediate 5-hydroxytryptophan. 

Acyl residues are usually activated by transfer to coenzyme A (2). In coenzyme A (see p. 12), pantetheine is linked to 3 -phos-pho-ADP by a phosphoric acid anhydride bond. Pantetheine consists of three components connected by amide bonds—pantoic acid, alanine, and cysteamine. The latter two components are biogenic amines formed by the decarboxylation of aspartate and cysteine, respectively. The compound formed from pantoic acid and p-alanine (pantothenic acid) has vitamin-like characteristics for humans (see p. 368). Reactions between the thiol group of the cysteamine residue and carboxylic acids give rise to thioesters, such as acetyl CoA. This reaction is strongly endergonic, and it is therefore coupled to exergonic processes. Thioesters represent the activated form of carboxylic adds, because acyl residues of this type have a high chemical potential and are easily transferred to other molecules. This property is often exploited in metabolism. 

The intermediates in fatty acid synthesis are linked to an acyl carrier protein. Specifically, they are linked to the sulfhydryl terminus of a phospho-pantetheine group. In the degradation of fatty acids, this unit is present as part of coenzyme A (p. 422), whereas, in their synthesis, it is attached to a serine residue of the acyl carrier protein (Figure 22,24). Thus, ACT, a single polypeptide chain of 77 residues, can be regarded as a giant prosthetic group, a macro ( loA. ... 

II cleaves acyl-CoAs of >6 carbons and P-hydroxyacyl-CoAs, but is unable to cleave acyl-pantetheine thioesters. The physiological function of thioesterases I and II is unknown. Null mutants have been constructed in both tesA and tesB, and the double-mutant strain generated. None of these strains has an observable growth phenotype, indicating that neither protein is essential. However, the tesAB double-null mutant still retains about 10% of the total wild-type thioesterase activity, indicating the existence of a third unidentified thioesterase in E. coli. 

Coenzyme A. CoA. C HjjNjO PjS mol wt 767.55. C 32.86%, H 4.73%, N 12.78%, O 33.35%, P 12.11%, S 4.18%, A co-factor in enzymatic acetyl transfer reactions. The molecule is built up from pantetheine [Lactobacillus bulgaricus factor consisting of pantothenic acid and cyste-amine (thioethylamine 0-mercaptoethylamine decarboxyl -ated cysteine)], adenosine, and phosphoric acid. Iscln from... 

Biological function P. is a biosynthetic precursor of coenzyme A. P. is present in coenzyme A bound to cys-teamine as pantetheine, C, H22N2O4S, Mr 278.37, [a] +12.9° (HjO). P. is considered to bdong to the vitamin B complex deficiency symptoms in chickens are loss of feathers. 

The flavane ring system is formed by the polyfunctional protein chalcone synthase from one molecule of a cinnamoyl CoA ester and 3 molecules malonyl CoA. The enzyme isolated from parsley (Petroselinum hortense) reacts with p-coumaroyl CoA and caffeoyl CoA as starter molecules (A 3.1). It uses the CoA esters as immediate substrates for the condensation reaction and contains neither an acyl carrier domain nor pantetheine. 

EC 2.7.1.33) to N-(i )-4 -phosphopantothenate. Activation of the carboxylate results from the addition of P-alanine (P-alanine is formed on decarboxylation of aspartate [Asp, D], EC 4.1.1.11), by cytidylate formation (cytosine triphosphate [CTP] is followed by coupling to L-cysteine (Cys, C) (EC 6.3.2.S) to produce N-[(i )-4 -phosphopantothienoyl]-L-< steine. Oxidation to the thioaldehyde with flavin mononucleotide (EMN FMNH2) allows decarboxylation of the latter with the formation of the corresponding enol. Then, reduction with nicotinamide adenine dinucleotide phosphate (NADPH/IT NADP) (EC 4.1.1.36) leads to 4-phosphopantetheine (pantetheine 4 -phosphate). 

Now, pantetheine itself (Scheme 12.110) was synthesized from the lactone that is, as shown in Scheme 12.110, when the easily oxidized thiol 7V-P-alanyl-2-mercaptoethylamine reacted with the chiral pantolactone in the absence of solvent at 100°C, pantetheine formed. The formation of the thiol 7V-P-alanyl-2-mercaptoethylamine and the reaction to form pantetheine began with the reaction of 2-bromoethylamine hydrobromide with benzylthiol. 

The resulting 2-benzylthioethylamine could be debenzylated by treatment with sodium in liquid ammonia. However, when 2-benzylthioethylamine was treated with carbobenzyloxy-P-alanine azide (prepared from carbobenzyloxy-P-alanylhydrazide by nitrosation), 2-benzylthio-7V-(carbobenzyloxy-P-alanyl)ethyl-amine formed. Reduction with sodium in liquid ammonia was sufficient to remove both the benzyl and carbobenzyloxy protecting groups and, as noted above, reaction with pantolactone yielded pantetheine. Phosphorylation to the mono- and diphosphates of pantetheine has been effected with the corresponding dibenzylphospho-nates (vide supra, ATP). 

NFS ninhydrin positive substances NEM N-ethylmaleimide ODC = ornithine decarboxylase 0-MT = 0-methylthreonine P = pantothenate PAP = phosphoadenosylphosphate PAPCA = phosphoadenosylphosphocysteic acid PAPS = phosphoadenosylphosphosulfate PCA = perchloric acid PCYM = pantetheine... 

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