Electrostatic Interactions Dictate Bile Salt Hydrolase Substrate Preference

Abstract

The human intestines are colonized by trillions of microbes, comprising the gut microbiota, which produce diverse small molecule metabolites and modify host metabolites, such as bile acids, that regulate host physiology. Biosynthesized in the liver, bile acids are conjugated with glycine or taurine and secreted into the intestines, where gut microbial bile salt hydrolases (BSHs) deconjugate the amino acid to produce unconjugated bile acids that serve as precursors for secondary bile acid metabolites. Among these include a recently discovered class of microbially-conjugated bile acids (MCBAs), wherein alternative amino acids are conjugated onto bile acids. To elucidate the metabolic potential of MCBAs, we performed detailed kinetic studies to investigate the preference of BSHs for host- and microbially-conjugated bile acids. We identified a BSH that exhibits positive cooperativity uniquely for MCBAs containing an aromatic sidechain. Further molecular modeling and phylogenetic analyses indicated that BSH preference for aromatic MCBAs is due to a substrate-specific cation-{rho}{varepsilon} interaction and is predicted to be widespread among human gut microbial BSHs. TOC graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/559308v2_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@11d6764org.highwire.dtl.DTLVardef@16efed0org.highwire.dtl.DTLVardef@1b13a7org.highwire.dtl.DTLVardef@1a7682e_HPS_FORMAT_FIGEXP M_FIG C_FIG