Xenobiotic/medium chain fatty acid: CoA ligase – a critical review on its role in fatty acid metabolism and the detoxification of benzoic acid and aspirin

ABSTRACT

Introduction: Activation of fatty acids by the acyl-CoA synthetases (ACSs) is the vital first step in fatty acid metabolism. The enzymatic and physiological characterization of the human xenobiotic/medium chain fatty acid: CoA ligases (ACSMs) has been severely neglected even though xenobiotics, such as benzoate and salicylate, are detoxified through this pathway.

Areas covered: This review will focus on the nomenclature and substrate specificity of the human ACSM ligases; the biochemical and enzymatic characterization of ACSM1 and ACSM2B; the high sequence homology of the ACSM2 genes (ACSM2A and ACSM2B) as well as what is currently known regarding disease association studies.

Expert opinion: Several discrepancies exist in the current literature that should be taken note of. For example, the single nucleotide polymorphisms (SNPs) reported to be associated with aspirin metabolism and multiple risk factors of metabolic syndrome are incorrect. Kinetic data on the substrate specificity of the human ACSM ligases are non-existent and currently no data exist on the influence of SNPs on the enzyme activity of these ligases. One of the biggest obstacles currently in the field is that glycine conjugation is continuously studied as a one-step process, which means that key regulatory factors of the two individual steps remain unknown.

KEYWORDS:

• ACSM
• acyl-coenzyme A
• aspirin
• benzoate
• glycine conjugation
• medium chain fatty acid
• CoA ligase
• salicylate

Article highlights

• The physiological role of the individual human ACSM ligases have not been thoroughly clarified.

• CoA activation by ACSM2B is important for the detoxification of benzoate and salicylate.

• The substrate specificity of ACSM2B for salicylate is very low when compared to benzoate, which might contribute to aspirin sensitivity.

• The influence of genetic variation on the enzyme activity of the individual ACSM ligases are unknown.

• The high exposure to xenobiotics in modern times might have a detrimental effect on the CoA activation and subsequent glycine conjugation of these compounds.

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Declaration of interest

Any opinion, finding and conclusion or recommendation expressed in this material is that of the authors and the NRF does not accept any liability in this regard. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

Research reported in this publication was supported by the South African Medical Research Council under a Self-Initiated Research Grant. This work is based on the research supported in part by the National Research Foundation of South Africa for the grant, Unique Grant No 99323.