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Research Themes Protein design

Microbiome: Insights into Secondary Bile Acid Synthesis

SBKB [doi:10.1038/sbkb.2012.158]
Featured Article - September 2013
Short description: Structural characterization of a gut microbe dehydrogenase illuminates cofactor specificity and mechanism of proton relay.

Crystal structure of BaiA2 bound to a putative NAD+-OH adduct. Secondary structure elements are represented as follows: helices in red, strands in yellow and loops in green. NAD is shown with C, N, P and O atoms in grey, blue, orange and red, respectively. The OH- of the adduct is shown as purple sphere. Figure courtesy of Scott Lesley.

While the main function of bile acids is the formation of micelles that aid in dietary fat processing, they also play key physiological roles through the activation of cellular receptors that regulate lipid, glucose and energy metabolism. Hence, modulating bile acid levels could be beneficial in treating metabolic disorders such as type 2 diabetes and cardiovascular diseases. The liver synthesizes the two primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA). Once released into the small intestinal lumen, they are further modified by bacteria to produce—through dehydroxylation—the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA).

To better understand secondary acid bile synthesis, Lesley and colleagues (PSI JCSG) solved the crystal structures of apo- (PDB 4IS2) and cofactor bound (PDB 4IS3) forms of the 3α-hydroxysteroid dehydrogenase BaiA2 from Clostridium scindens. C. scindens is part of the “core microbiome” and a member of a select group of microbes that harbor metabolic pathways for synthesizing secondary bile acids. BaiA2 catalyzes the second step in LCA synthesis by dehydrogenating CDCA-CoA (coenzyme A) to form the intermediate 3-oxo-CDCA-CoA. The authors also report the steady-state kinetic characterization of BaiA2 and the closely related BaiA1, providing the first structure-function study of a human gut microbial enzyme involved in the early steps of secondary bile acid synthesis.

BaiA2 is a single-domain protein adopting a characteristic Rossmann fold, with a doubly wound βαβαβ motif and distinct binding sites for substrate and nicotinamide adenine dinucleotide (NAD+) cofactor. Both apo- and NAD+-bound BaiA2 form a crystallographic tetramer, also observed in solution. While previous studies had suggested that either NAD+ or NADP+ cofactors could be used, the preferential utilization of NAD+ could be attributed to conformational restriction exerted by Glu42, which is located in the cofactor binding site. The cofactor-bound structure also revealed the presence of a nicotinamide-hydroxyl ion (NAD+-OH) adduct, the location of which suggests an involvement in proton relay, instead of the previously proposed role in hydride transfer reaction.

In addition to providing important mechanistic details of this essential synthetic pathway, the structural features uncovered by this work could eventually be used to design modulators of secondary bile acid levels in the human intestine.

Stéphane Larochelle

References

  1. S. Bhowmik et al. Structural and functional characterization of BaiA, An enzyme involved in secondary bile acid synthesis in human gut microbe.
    Proteins. (8 July 2013). doi:10.1002/prot.24353

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