Coenzyme A Analogs. Synthesis of D-Oxypantetheine-4' Phosphate and Oxy-Coenzyme A<sup>1a,b</sup>

Miller, T.; Rowley, Gerald L.; Stewart, Charles J.

doi:10.1021/ja00962a037

Cited by 22 publications

(17 citation statements)

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“…Compound 48 and oxypantetheine were postulated to exert their antimicrobial effect by being converted to CoA analogues that compete with CoA for binding to CoA‐utilizing enzymes (Stewart et al ., 1955). The CoA analogue predicted to result from the metabolism of oxypantetheine was reported to compete with CoA, and to inhibit its acetylation in a phosphotransacetylase reaction (Miller et al ., 1966), lending support to this hypothesis. Furthermore, Stewart & Ball (1966) showed that CoA biosynthesis enzymes extracted from beef liver acted on the phosphorylated form of oxypantetheine, yielding the corresponding CoA analogue.…”

Section: Pantetheine/pantethine Analogues As Antibacterial Agentsmentioning

confidence: 99%

Coenzyme A biosynthesis: an antimicrobial drug target

Spry¹,

Kirk²,

Saliba³

2008

FEMS Microbiol Rev

242

260

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Pantothenic acid, a precursor of coenzyme A (CoA), is essential for the growth of pathogenic microorganisms. Since the structure of pantothenic acid was determined, many analogues of this essential metabolite have been prepared. Several have been demonstrated to exert an antimicrobial effect against a range of microorganisms by inhibiting the utilization of pantothenic acid, validating pantothenic acid utilization as a potential novel antimicrobial drug target. This review commences with an overview of the mechanisms by which various microorganisms acquire the pantothenic acid they require for growth, and the universal CoA biosynthesis pathway by which pantothenic acid is converted into CoA. A detailed survey of studies that have investigated the inhibitory activity of analogues of pantothenic acid and other precursors of CoA follows. The potential of inhibitors of both pantothenic acid utilization and biosynthesis as novel antibacterial, antifungal and antimalarial agents is discussed, focusing on inhibitors and substrates of pantothenate kinase, the enzyme catalysing the rate-limiting step of CoA biosynthesis in many organisms. The best strategies are considered for identifying inhibitors of pantothenic acid utilization and biosynthesis that are potent and selective inhibitors of microbial growth and that may be suitable for use as chemotherapeutic agents in humans.

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Section: Pantetheine/pantethine Analogues As Antibacterial Agentsmentioning

confidence: 99%

Coenzyme A biosynthesis: an antimicrobial drug target

Spry¹,

Kirk²,

Saliba³

2008

FEMS Microbiol Rev

242

260

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“…The traditional method for resolving isomers of CoA-containing compounds, ion exchange chromatography (1,2,14,34), is often lengthy, does not achieve base-line resolution, and thus may have hampered investigations into isomers of CoA (19). We report here an efficient HPLC methodology that achieves base line resolution of CoA and acyl-CoA isomers.…”

Section: Mass Spectrometric Structural Characterization Ofmentioning

confidence: 99%

Iso-coenzyme A

Burns

Gelbaum

Sullards

et al. 2005

Journal of Biological Chemistry

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Iso-coenzyme A is an isomer of coenzyme A in which the monophosphate is attached to the 2-carbon of the ribose ring. Although iso-CoA was first reported in 1959 (Moffatt, J. G., and Khorana, H. G. (1959) J. Am. Chem. Soc. 81, 1265-1265) to be a by-product of the chemical synthesis of CoA, relatively little attention has been focused on iso-CoA or on acyl-iso-CoA compounds in the literature. We now report structural characterizations of iso-CoA, acetyl-iso-CoA, acetoacetyl-iso-CoA, and ␤-hydroxybutyryl-iso-CoA using mass spectrometry (MS), tandem MS, and homonuclear and heteronuclear NMR analyses. Although the 2-phosphate isomer of malonyl-CoA was recently identified in commercial samples, previous characterizations of iso-CoA itself have been based on chromatographic analyses, which ultimately rest on comparisons with the degradation products of CoA and NADPH or have been based on assumptions regarding enzyme specificity. We describe a high performance liquid chromatography methodology for separating the isomers of several CoA-containing compounds. We also report here the first examples of isoCoA-containing compounds acting as substrates in enzymatic acyl transfer reactions. Finally, we describe a simple synthesis of iso-CoA from CoA, which utilizes ␤-cyclodextrin to produce iso-CoA with high regioselectivity, and we demonstrate a plausible mechanism that accounts for the existence of iso-CoA isomers in commercial preparations of CoA-containing compounds. We anticipate that these results will provide methodology and impetus for investigating iso-CoA compounds as potential pseudo-substrates or inhibitors of the >350 known CoA-utilizing enzymes.Iso-coenzyme A is an isomer of coenzyme A in which the monophosphate is attached to the 2Ј-carbon of the ribose ring. Iso-CoA was first reported in 1959 by Moffatt and Khorana (1, 2) to be a by-product of the chemical synthesis of CoA. The final step of this synthesis entailed acid-catalyzed hydrolysis of cyclic coenzyme A (Scheme 1) to produce a 50:50 mixture of two products that were separated using epicholorohydrin triethanolamine (ECTEOLA) cellulose ion exchange chromatography (1, 2). Direct structural analysis was not readily available in 1959; consequently, the authors deduced the structure of isoCoA by establishing that, in contrast to CoA, iso-CoA was not a substrate for the enzyme phosphotransacetylase (1, 2). Moffatt and Khorana also used paper chromatography of phosphodiesterase hydrolysates to show that enzymatic hydrolysis of isoCoA produces adenosine-2Ј,5Ј-diphosphate, exclusively (1, 2). Since the original work of Moffatt and Khorana was done, four additional chemical syntheses of CoA have been reported (3-8), all of which produce cyclic CoA as the penultimate product; cyclic CoA is then hydrolyzed either chemically to produce a mixture of CoA and iso-CoA (1, 2, 4 -6, 8) or enzymatically with ribonuclease T2 to produce CoA regioselectively (3-7).Recently, Minkler et al. (9) observed the 2Ј-phosphate isomer of malonyl-CoA in commercial samples. These authors ...

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“…Numerous coenzyme A analogues have been synthesised by chemical or chemoenzymatic methods including seleno-CoA, [19] oxy-CoA, [20] decysteamine-CoA, [21] desulfo-CoA, [22] succinylCoA, [23] crotonyl-CoA, [24] bromoacetyl-CoA, [25] S-acetonyl-CoA, [26] S-(3-oxobutyl)-CoA, [27] acetonyldethio-CoA, [28] methylmalonylcarba(dethia)-CoA, [29] keto-CoA [21] and guano-CoA. [30] The enzymatic synthesis of CoA analogues was first achieved in 1964 when Michelson utilised ribonuclease T 2 .…”

mentioning

confidence: 99%

Complementary PCAF–Coenzyme A Mutagenesis: Chemoenzymatic Synthesis of a Novel Enlarged Coenzyme A Analogue and Evaluation of Its Biological Activity

et al. 2010

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Coenzyme A Analogs. Synthesis of D-Oxypantetheine-4' Phosphate and Oxy-Coenzyme A^1a,b

Cited by 22 publications

References 1 publication

Coenzyme A biosynthesis: an antimicrobial drug target

Coenzyme A biosynthesis: an antimicrobial drug target

Iso-coenzyme A

Complementary PCAF–Coenzyme A Mutagenesis: Chemoenzymatic Synthesis of a Novel Enlarged Coenzyme A Analogue and Evaluation of Its Biological Activity

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Coenzyme A Analogs. Synthesis of D-Oxypantetheine-4' Phosphate and Oxy-Coenzyme A1a,b

Cited by 22 publications

References 1 publication

Coenzyme A biosynthesis: an antimicrobial drug target

Coenzyme A biosynthesis: an antimicrobial drug target

Iso-coenzyme A

Complementary PCAF–Coenzyme A Mutagenesis: Chemoenzymatic Synthesis of a Novel Enlarged Coenzyme A Analogue and Evaluation of Its Biological Activity

Contact Info

Product

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About

Coenzyme A Analogs. Synthesis of D-Oxypantetheine-4' Phosphate and Oxy-Coenzyme A^1a,b