Functional role of a distal (3′-phosphate) group of CoA in the recombinant human liver medium-chain acyl-CoA dehydrogenase-catalysed reaction

Peterson, Kevin; Srivastava, D. K.

doi:10.1042/bj3250751

Cited by 12 publications

(5 citation statements)

References 26 publications

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“…The majority of the substrate-binding energy comes from the CoA moiety of the substrate that is not directly involved in any of the chemical steps, as seen with 3-oxoacid CoA-transferase (41). It has been shown that 3′phosphate group of CoA moiety contributes 5.2 kJ/mol in the binding free energy with human MCAD (42). Also, the K m of glutaryl-patetheine is some 590-fold higher than glutaryl-CoA reflecting the contribution of the 3′-phospho-5′ADP moiety of the CoA thiolester substrate in the binding process (13).…”

Section: Resultsmentioning

confidence: 99%

Crystal Structures of Human Glutaryl-CoA Dehydrogenase with and without an Alternate Substrate: Structural Bases of Dehydrogenation and Decarboxylation Reactions^,

Wang

Paschke

et al. 2004

Biochemistry

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Acyl-CoA dehydrogenases (ACDs) are a family of flavoenzymes that metabolize fatty acids and some amino acids. Of nine known ACDs, glutaryl-CoA dehydrogenase (GCD) is unique: in addition to the alpha,beta-dehydrogenation reaction, common to all ACDs, GCD catalyzes decarboxylation of glutaryl-CoA to produce CO(2) and crotonyl-CoA. Crystal structures of GCD and its complex with 4-nitrobutyryl-CoA have been determined to 2.1 and 2.6 A, respectively. The overall polypeptide folds are the same and similar to the structures of other family members. The active site of the unliganded structure is filled with water molecules that are displaced when enzyme binds the substrate. The structure strongly suggests that the mechanism of dehydrogenation is the same as in other ACDs. The substrate binds at the re side of the FAD ring. Glu370 abstracts the C2 pro-R proton, which is acidified by the polarization of the thiolester carbonyl oxygen through hydrogen bonding to the 2'-OH of FAD and the amide nitrogen of Glu370. The C3 pro-R proton is transferred to the N(5) atom of FAD. The structures indicate a plausible mechanism for the decarboxylation reaction. The carbonyl polarization initiates decarboxylation, and Arg94 stabilizes the transient crotonyl-CoA anion. Protonation of the crotonyl-CoA anion occurs by a 1,3-prototropic shift catalyzed by the conjugated acid of the general base, Glu370. A tight hydrogen-bonding network involving gamma-carboxylate of the enzyme-bound glutaconyl-CoA, with Tyr369, Glu87, Arg94, Ser95, and Thr170, optimizes orientation of the gamma-carboxylate for decarboxylation. Some pathogenic mutations are explained by the structure. The mutations affect protein folding, stability, and/or substrate binding, resulting in inefficient/inactive enzyme.

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Section: Resultsmentioning

confidence: 99%

Crystal Structures of Human Glutaryl-CoA Dehydrogenase with and without an Alternate Substrate: Structural Bases of Dehydrogenation and Decarboxylation Reactions^,

Wang

Paschke

et al. 2004

Biochemistry

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“…Several acyl-dephospho-CoAs have been synthesized in vitro ( 26,27 ), and valproyl-dephospho-CoA has been identifi ed in isolated rat liver mitochondria from CoA trapping reagent (valproate), suggesting that both the phosphoand dephospho-CoA forms are biologically active ( 28 ). The absence of the 3 ′ -phosphate group on the ribose moiety of acyl-dephospho-CoAs is the only difference compared with their corresponding acyl-CoAs.…”

Section: Lc-ms/ms Is the Most Sensitive Methods To Analyze Acylcoas Anmentioning

confidence: 99%

Novel approach in LC-MS/MS using MRM to generate a full profile of acyl-CoAs: discovery of acyl-dephospho-CoAs

Zhang

Berthiaume

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org Acyl-CoAs are a class of important molecules that play essential roles in many physiological processes ( 1 ), such as fatty acid oxidation, lipid synthesis/remodeling, ketone body synthesis, xenobiotic metabolism, and signaling pathways. Classically, acyl-CoAs such as free CoA, acetyl-CoA, and malonyl-CoA are recognized as regulators of metabolic fl ux. The ratio of acetyl-CoA versus free CoA tightly regulates glycolysis and fatty acid oxidation. Malonyl-CoA attenuates fatty acid oxidation by inhibiting acyl-CoA transport into the mitochondrion for oxidation and is utilized in fatty acid synthesis when its concentration is elevated ( 2 ). Many proteins and genes are dynamically regulated by deacylation and acylation via various acyl-CoAs, such as acetyl-CoA, succinyl-CoA, palmitoyl-CoA, etc. ( 3 ). However, acyl-CoAs present in the cell are diverse and may involve molecules beyond fatty acids and their oxidized derivatives. The metabolism of xenobiotics can also lead to the formation of acyl-CoAs, as demonstrated in our previous work on the metabolism of 4-hydroxy acids from C 4 to C 11 in perfused rat liver. The identifi cation of these novel acyl-CoAs extends our understanding of the new catabolic pathways involved in the disposal of 4-hydroxy acids including drugs of abuse and lipid peroxidation products ( 4-8 ).Acyl-CoAs are exclusive to the intracellular metabolites, and the profi le of these biomolecules is indicative of the local metabolic status. Each organ has its specifi c physiological roles with different energetic demands, and therefore, would be expected to exhibit a unique acyl-CoA profi le. The heart preferentially utilizes fatty acids to meet the ATP demand of mechanical contraction. Glucose and/or ketone bodies serve as the primary substrate of the brain for energy

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“…7 A). It has been demonstrated that the 3′-phosphate group of acyl-CoA plays a significant role in human medium-chain acyl-CoA dehydrogenase 45 , 46 . In this case, the 3′-phosphate group makes an enthalpic contribution derived from van der Waals interactions between the 3′-phosphate group and the surrounding protein moiety.…”

Section: Discussionmentioning

confidence: 99%

Acyl-CoA thioesterase activity of peroxisomal ABC protein ABCD1 is required for the transport of very long-chain acyl-CoA into peroxisomes

Kawaguchi

Mukai

Watanabe

et al. 2021

Sci Rep

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The ABCD1 protein, one of the four ATP-binding cassette (ABC) proteins in subfamily D, is located on the peroxisomal membrane and is involved in the transport of very long chain fatty acid (VLCFA)-CoA into peroxisomes. Its mutation causes X-linked adrenoleukodystophy (X-ALD): an inborn error of peroxisomal β-oxidation of VLCFA. Whether ABCD1 transports VLCFA-CoA as a CoA ester or free fatty acid is controversial. Recently, Comatose (CTS), a plant homologue of human ABCD1, has been shown to possess acyl-CoA thioesterase (ACOT) activity, and it is suggested that this activity is required for transport of acyl-CoA into peroxisomes. However, the precise transport mechanism is unknown. Here, we expressed human His-tagged ABCD1 in methylotrophic yeast, and characterized its ACOT activity and transport mechanism. The expressed ABCD1 possessed both ATPase and ACOT activities. The ACOT activity of ABCD1 was inhibited by p-chloromercuribenzoic acid (pCMB), a cysteine-reactive compound. Furthermore, we performed a transport assay with ABCD1-containing liposomes using 7-nitro-2–1,3-benzoxadiazol-4-yl (NBD)-labeled acyl-CoA as the substrate. The results showed that the fatty acid produced from VLCFA-CoA by ABCD1 is transported into liposomes and that ACOT activity is essential during this transport process. We propose a detailed mechanism of VLCFA-CoA transport by ABCD1.

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Functional role of a distal (3′-phosphate) group of CoA in the recombinant human liver medium-chain acyl-CoA dehydrogenase-catalysed reaction

Cited by 12 publications

References 26 publications

Crystal Structures of Human Glutaryl-CoA Dehydrogenase with and without an Alternate Substrate: Structural Bases of Dehydrogenation and Decarboxylation Reactions^,

Crystal Structures of Human Glutaryl-CoA Dehydrogenase with and without an Alternate Substrate: Structural Bases of Dehydrogenation and Decarboxylation Reactions^,

Novel approach in LC-MS/MS using MRM to generate a full profile of acyl-CoAs: discovery of acyl-dephospho-CoAs

Acyl-CoA thioesterase activity of peroxisomal ABC protein ABCD1 is required for the transport of very long-chain acyl-CoA into peroxisomes

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Functional role of a distal (3′-phosphate) group of CoA in the recombinant human liver medium-chain acyl-CoA dehydrogenase-catalysed reaction

Cited by 12 publications

References 26 publications

Crystal Structures of Human Glutaryl-CoA Dehydrogenase with and without an Alternate Substrate: Structural Bases of Dehydrogenation and Decarboxylation Reactions,

Crystal Structures of Human Glutaryl-CoA Dehydrogenase with and without an Alternate Substrate: Structural Bases of Dehydrogenation and Decarboxylation Reactions,

Novel approach in LC-MS/MS using MRM to generate a full profile of acyl-CoAs: discovery of acyl-dephospho-CoAs

Acyl-CoA thioesterase activity of peroxisomal ABC protein ABCD1 is required for the transport of very long-chain acyl-CoA into peroxisomes

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Crystal Structures of Human Glutaryl-CoA Dehydrogenase with and without an Alternate Substrate: Structural Bases of Dehydrogenation and Decarboxylation Reactions^,

Crystal Structures of Human Glutaryl-CoA Dehydrogenase with and without an Alternate Substrate: Structural Bases of Dehydrogenation and Decarboxylation Reactions^,