Bile salt hydrolases: Structure and function, substrate preference, and inhibitor development

Abstract

The worldwide trend of limiting the use of antibiotic growth promoters (AGPs) in animal production creates challenges for the animal feed industry, thus necessitating the development of effective non-antibiotic alternatives to improve animal performance. Increasing evidence has shown that the growth-promoting effect of AGPs is highly correlated with the reduced activity of bile salt hydrolase (BSH, EC 3.5.1.24), an intestinal bacteria-producing enzyme that has a negative impact on host fat digestion and energy harvest. Therefore, BSH inhibitors may become novel, attractive alternatives to AGPs. Detailed knowledge of BSH substrate preferences and the wealth of structural data on BSHs provide a solid foundation for rationally tailored BSH inhibitor design. This review focuses on the relationship between structure and function of BSHs based on the crystal structure, kinetic data, molecular docking and comparative structural analyses. The molecular basis for BSH substrate recognition is also discussed. Finally, recent advances and future prospectives in the development of potent, safe, and cost-effective BSH inhibitors are described.

Keywords: BSH inhibitors; animal feed supplements; antibiotic growth promoters; bile salt hydrolase; fat digestion; structural basis for the substrate preference.

Figure 1

Structures of a variety of substrates and inhibitors of BSHs. (A) General structures of bile acids. As an example, the structure of glycocholic acid is shown. The bond hydrolyzed by BSH is indicated by an arrow; rings A to D are highlighted in blue; OH* and OH** represent hydroxyl groups absent in deoxycholic and chenodeoxycholic acids, respectively. (B) Structures of BSH inhibitors riboflavin and phenethyl caffeate.

Figure 2

Family tree of BSH members with characterized substrate preference. BSHs exhibiting a preference for glyco‐ and tauro‐conjugated bile salts are highlighted by red and blue, respectively; while BSHs equally hydrolyzing both tauro‐ and glyco‐conjugated bile salts are colored in orange.

Figure 3

Multiple sequence alignment of BSHs listed in Table 1. BSHs with substrate preference for GC, TC/GC, and TC are colored in red, orange, and blue, respectively. Active sides are highlighted by yellow. Key amino acid residues potentially involved in substrate selectivity of Cp13_CBAH1, BlSBT2928_BSH, and LgFR4_BSH are highlighted by green, purple, and pink, respectively. Residues at Position 68 are indicated by a five‐pointed star. Secondary structure elements of BlSBT2928_BSH (above) and Cp13_CBAH1 (below) are also shown.

Figure 4

Comparison of the binding pocket loops of Cp13_CBAH1 (green; PDB ID: 2bjf), BlSBT2928_BSH (red; PDB ID: 2hez), LsB‐30514_BSH (yellow; PDB ID: 5hke), and EfNCIM2403_BSH (blue; PDB ID: 4wl3). TAU, taurine; DXC, deoxycholic acid. The six residues (Cys2, Arg18, Asp21, Asn82, Asn173, and Arg226) involved in the catalytic reaction in BlSBT2928_BSH are shown.