Disease relevance of COASY

• The human gene localizes to chromosome 17q12-21 and contains regions with sequence similarity to the monofunctional Escherichia coli DPCK and PPAT [1].
• This enzyme forms a tightly packed trimer in its crystal state, in contrast to its observed monomeric structure in solution and to the monomeric, homologous DPCK structure from Haemophilus influenzae [2].

High impact information on COASY

• CODH would more properly be called carbon monoxide dehydrogenase-acetyl CoA synthase as it catalyzes oxidation of CO to CO2 and the synthesis of acetyl CoA [3].
• Palmitate-induced apoptosis was enhanced by the fat oxidation inhibitor etomoxir, whereas it was reduced by fatty-acyl CoA synthase inhibitor triacsin C [4].
• Furthermore, addition of either the microsomal triglyceride transfer protein inhibitor or triacsin C, an inhibitor of acyl-CoA synthase, completely abrogated the oleate-dependent increase in apo(a) secretion [5].
• Treating cells with the acyl-coenzyme A synthase inhibitor triacsin C, or the AMP kinase activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside that redirect lipid partitioning to oxidation, curtailed glucolipotoxicity [6].
• In contrast, in vitro studies show that the major splice variant (lacking exon 4-encoded sequence) produces a functional enzyme, albeit with slightly reduced activity and with affinity for the ATP-specific, beta subunit of succinyl CoA synthase, comparable to that of mature ALAS2 [7].

Biological context of COASY

• Here, we describe the existence of a novel CoA synthase isoform, which is the product of alternative splicing and possesses a 29aa extension at the N-terminus [8].
• Multiple alignment of orthologous DPCK sequences reveals a set of highly conserved residues in the vicinity of the nucleotide/CoA binding site [2].
• Specific interaction between S6K1 and CoA synthase: a potential link between the mTOR/S6K pathway, CoA biosynthesis and energy metabolism [9].
• Transcriptional activation of peroxisomal acyl-CoA oxidase by peroxisomal proliferators was inhibited in the presence of transfected functional acyl-CoA synthase [10].
• Up-regulation by androgens of mRNA expression of HMG coenzyme A synthase and reductase, acetyl coenzyme A carboxylase (ACC), glycerol 3-phosphate acyl transferase (GPAT), and FAR-17c (stearoyl coenzyme A desaturase homologous), was demonstrated [11].

Associations of COASY with chemical compounds

• CoA synthase is a bifunctional enzyme which mediates the final stages of CoA biosynthesis [8].
• Work on the hydrogenases was expanded to include modeling of acetyl Co-A synthase, leading to the preparation of mixed valence Ni(2) models containing bound CO substrate [12].
• In an effort to overcome this limitation, truncated derivatives of 1 were designed, synthesized and tested as p300HAT inhibitors as well as substrates for the CoA biosynthetic bifunctional enzyme phosphopantetheine adenylyltransferase-dephospho-CoA kinase (PPAT/DPCK) [13].

Other interactions of COASY

• We demonstrate for the first time that CoA synthase associates specifically with S6K1 [9].

Analytical, diagnostic and therapeutic context of COASY

• In previous studies, we have reported molecular cloning, biochemical characterization, and subcellular localization of CoA synthase (CoASy) [8].
• New guidelines governing drug preparation ('NBP' standards of preparation) published in Italian Pharmacopoeia (2002, XI Edition) have been mandatory since 2004 and set out rules for proper pharmacy practice applicable also to antineoplastic drug preparations [14].

References