Converging on a mechanism for choline degradation

Abstract

In PNAS, Craciun and Balskus (1) combine biochemical intuition with modern genome mining techniques to discover the elusive enzyme responsible for catalyzing the degradation of choline ( 1 , Scheme 1). Choline is an essential nutrient in higher organisms that is required for the biosynthesis of the neurotransmitter acetylcholine and the head group of several phospholipids, and that serves as a source of the methyl groups for methionine and S -adenosylmethionine (2). In humans and other mammals, choline is catabolized to trimethylamine (TMA; 2 , Scheme 1) by symbiotic gut microbes, and irregularities in choline and TMA metabolism have been linked to liver and cardiovascular diseases, atherosclerosis, and deficiencies in fetal brain development (3⇓–5). TMA derived from choline is also a substrate for methanogenesis by marine microorganisms and, as such, contributes to global production of the greenhouse gas methane. Scheme 1. Mechanistic similarities in the catabolism of choline, ethanolamine, and glycerol; in each case, the bonds highlighted in red are cleaved by enzyme-mediated radical chemistry that results in a 1,2-migration. Scheme 2. Putative chemical mechanism of ethanolamine degradation by the adenosylcobalamin-dependent enzyme, ethanolamine ammonia lyase (EAL). To identify the unknown choline degrading enzyme, which has eluded researchers for more than a century, the authors postulated that the conversion of choline to TMA and acetaldehyde ( 3 , Scheme 1) may share mechanistic similarities to the well-studied catabolism of ethanolamine ( 4 , Scheme 1) to ammonia and acetaldehyde by bacterial enzymes encoded in the ethanolamine utilization ( eut ) gene cluster (6⇓–8). In ethanolamine degradation, C-N bond cleavage is carried out by the adenosylcobalamin (AdoCbl)-dependent enzyme, ethanolamine ammonia lyase (EAL), encoded by the eutBC genes (6). After the EAL-catalyzed cleavage of the C-N bond of … [↵][1]1To whom correspondence should be addressed. E-mail: vddonk{at}illinois.edu. [1]: #xref-corresp-1-1