An inhibitor to target MCAD

What is it about?

The natural plant-derived poison hypoglycin A acts by 'lethal synthesis'. Being an amino acid it is treated like leucine and successfully undergoes both tansamination and oxidative decarboxylation in vivo to give methylene cyclopropyl acetic acid (MCPA). This is a suicide inhibitor for short-chain acyl-CoA dehydrogenase (SCAD) and causes the potential fatal symptoms of 'Jamaican vomiting sickness' casued by eating unripe ackee fruit. Fatty acid beta-oxidation uses as set of enzymes of changing chain-length specificity to cover the full range and here we attempted successfully to make an analogue of MCPA with a C6 extension. The corresponding CoA derivative is a selective inhibitor for MCAD and LCAD, showing little inhibitory effect on SCAD.

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Why is it important?

Selective inhibitors are potentially valuable tools for exploring fatty acid metabolism. Unfortunately this inhibitor is not generally available and its use would still rely on de novo synthesis by a competent chemist.