Pantetheine, structure

Coenzyme A (abbreviated CoA or CoASH, 6) was discovered by Lipmann in the 1940s, and its structure was first reported in 1953 (2, 3). The structure of CoA consists of 3 -phosphoadenosine and pantetheine, linked by a pyrophosphate group (Fig. 1). The pantetheine moiety is derived from pantothenic acid 1, also known as vitamin B5. CoA and its... 

The isolated TE domain from the tyrocidine (tyc) NRPS has recently been shown to catalyze the macrocyclization of unnatural substrates to generate a variety of cyclic peptides. In conjunction with standard solid-phase peptide synthesis, Walsh and coworkers demonstrated a broad substrate tolerance for peptidyl-N-acetylcysteamine thioesters by the tyrocidine TE [41,42], Cyclization of peptide analogs, where individual amino acids were replaced with ethylene glycol units, was observed with high efficiency. In addition, hydroxyacid starter units were readily cyclized by the isolated TE domain to form nonribosomal peptide-derived macrolactones. More recently, Walsh and coworkers have demonstrated effective cyclization of PEGA resin-bound peptide/polyketide hybrids by the tyrocidine TE domain [43], Utilization of a pantetheine mimic for covalent attachment of small molecules to the resin, serves as an appropriate recognition domain for the enzyme. As peptide macrocyclizations remain challenging in the absence of enzymatic assistance, this approach promises facile construction of previously unattainable structures. 

Figure 10 The biosynthetic thioiase from Z. ramigera. (a) Thioiase structure showing the tetramerization motif, (b) Surface representation showing the CoA-binding site and the tunnei that provides access for the (acyl)-pantetheine to the active site, (c) The AcAc-CoA group surrounded by active site residues. Note that in this structure the catalytic cysteine (C89) has been mutated to an aianine.

Thiol group, sulfkydryl group, metcapto gro -SH, the functional group of thiols (mercaptans), i.e. the functional group of RSH, where R is the remainder of the molecule. T.g. may be structurally important as in Thiol enzymes (see), or functionally important as in Coenzyme A (see), Pantetheine-4 -phosphate (see), Lipoic acid (see), Thioredoxin (see), etc. The functional form of lipoic and thioredoxin is a dithiol. 

Coenzyme A is a complex organic molecule with a nucleotide portion of adenine, ribose and phosphoryl groups linked through a pyrophosphoryl bridge to an unusual peptide, pantetheine. This structure has a branched-chain dihydroxy acid, pantoic acid, linked to /3-aIanine which in turn is bonded to thioethylamine. In spite of the complexity of the coenzyme A... 

The C-ierminal boundary of the adenylate domain has been deduced from limited proteolysis and sequence alignments (69), which have identified also sirnilarities of structural organization of the adjacent pantetheine-attaching region (motif J) with various acyl canier proteins. 

Figure 20.1 Structure of pantothenic acid and bound form coenzyme A (CoA), phosphopantetheine and pantetheine.

Structure of Coemyme A. The elucidation of the structure of CoA depended heavily on d radation by specific enzymes. The phosphate on carbon 3 of the adenosine was shown to be a monoester phosphate by hydrolysis with prostate phosphomonoesterase. The localization of the monoester at the 3 position was established by its sensitivity to a b nucleotidase that attacks only nucleoside 3 -pbosphates, not 2 - or 5 -phosphates. The original CoA molecule or the phosphatase product, depbospho CoA, can be split by nucleotide pyrophosphatases from potato or snake venom. These reactions permitted the identification of the adenosine phosphate portion of the molecule. The position of the phosphate on pantothenic acid cannot be determined enzymatically, but was established by studies on the synthesis of CoA from synthetic phos-phorylated pantetheines. Pantetheine is split to thiolethanolamine and pantothenic acid by an enzyme found in liver and kidney. This enzyme also attacks larger molecules, including CoA. 

Snell el al. examined a sample of coenzyme A supplied by Lipmann for growth factor activity and found it inactive, but coenzyme A treated with intestinal phosphatase was active. Pantetheine (or pantothine) thus arises by enzymic breakdown of coenzyme A. It must therefore be preformed in the coenzyme A molecule. The following structure, proposed by Lipmann, is based on enzymic degradation and resynthesis and may be regarded as established. 

The chemical structure of coenzyme A is considerably more complex than that of the preceding coenzymes. It is helpful to divide it mentally into adenosines, 5 -diphosphate and pantetheine phosphate. Pantetheine is a growth factor for several microorganisms, e.g. Lactobacillus bulgaricus. It, in turn, consists of pantoic acid, 3-alanine, and mercaptoethylamine, the decarboxylation product of cysteine. The pantetheine component of CoA therefore contains three constituents in amide linkage. 

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