NDLI: Structural and Functional Characterization of BaiA, An Enzyme Involved in Secondary Bile Acid Synthesis in Human Gut Microbe

Content Provider	PubMed Central
Author	Bhowmik, Shiva Jones, David H. Chiu, Hsien-po Park, In-hee Chiu, Hsiu-ju Axelrod, Herbert L. Farr, Carol L. Tien, Henry J. Sanjay, Agarwalla Lesley, Scott A.
Abstract	Despite significant influence of secondary bile acids on human health and disease, limited structural and biochemical information is available for the key gut microbial enzymes catalyzing its synthesis. Herein, we report apo- and co-factor bound crystal structures of BaiA2, a short chain dehydrogenase/reductase from Clostridium scindens VPI 12708 that represent the first protein structure of this pathway. The structures elucidated the basis of co-factor specificity and mechanism of proton relay. A conformational restriction involving Glu42 located in the co-factor binding site seems crucial in determining co-factor specificity. Limited flexibility of Glu42 results in imminent steric and electrostatic hindrance with 2′-phosphate group of NADP(H). Consistent with crystal structures, steady-state kinetic characterization performed with both BaiA2 and BaiA1, a close homolog with 92% sequence identity, revealed specificity constant (kcat /KM) of NADP+ at least an order of magnitude lower than NAD+. Substitution of Glu42 with Ala improved specificity towards NADP+ by 10- fold compared to wild type. The co-factor bound structure uncovered a novel nicotinamide-hydroxyl ion (NAD+-OH−) adduct contraposing previously reported adducts. The OH− of the adduct in BaiA2 is distal to C4 atom of nicotinamide and proximal to 2′-hydroxyl group of the ribose moiety. Moreover, it is located at intermediary distances between terminal functional groups of active site residues Tyr157 (2.7 Å) and Lys161 (4.5 Å). Based on these observations we propose an involvement of NAD+-OH− adduct in proton relay instead of hydride transfer as noted for previous adducts.
Related Links	http://dx.doi.org/10.1002/prot.24353
Ending Page	229
Page Count	14
Starting Page	216
File Format	PDF
ISSN	08873585
e-ISSN	10970134
Journal	Proteins
Issue Number	2
Volume Number	82
Language	English
Publisher Date	2014-02-01
Access Restriction	Open
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Structural Biology Biochemistry Molecular Biology

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