Evolutionary Analysis of Bile Acid-Conjugating Enzymes Reveals a Complex Duplication and Reciprocal Loss History.

First Authors Bogdan Kirilenko
Authors Bogdan Kirilenko, Lee R Hagey, Stephen Barnes, Charles N Falany, Michael Hiller
Corresponding Authors Michael Hiller
Last Authors Michael Hiller
Journal Name Genome biology and evolution (Genome Biol Evol)
Volume 11
Issue 11
Page Range 3256-3268
PubMed ID 31670760
WebOfScience Link WOS:000504929400019
Open Access true
Print Publication Date 2019-11-01
Online Publication Date
Abstract To fulfill their physiological functions, bile acids are conjugated with amino acids. In humans, conjugation is catalyzed by bile acid coenzyme A: amino acid N-acyltransferase (BAAT), an enzyme with a highly conserved catalytic triad in its active site. Interestingly, the conjugated amino acids are highly variable among mammals, with some species conjugating bile acids with both glycine and taurine, whereas others conjugate only taurine. The genetic origin of these bile acid conjugation differences is unknown. Here, we tested whether mutations in BAAT's catalytic triad could explain bile acid conjugation differences. Our comparative analysis of 118 mammals first revealed that the ancestor of placental mammals and marsupials possessed two genes, BAAT and BAATP1, that arose by a tandem duplication. This duplication was followed by numerous gene losses, including BAATP1 in humans. Losses of either BAAT or BAATP1 largely happened in a reciprocal fashion, suggesting that a single conjugating enzyme is generally sufficient for mammals. In intact BAAT and BAATP1 genes, we observed multiple changes in the catalytic triad between Cys and Ser residues. Surprisingly, although mutagenesis experiments with the human enzyme have shown that replacing Cys for Ser greatly diminishes the glycine-conjugating ability, across mammals we found that this residue provides little power in predicting the experimentally measured amino acids that are conjugated with bile acids. This suggests that the mechanism of BAAT's enzymatic function is incompletely understood, despite relying on a classic catalytic triad. More generally, our evolutionary analysis indicates that results of mutagenesis experiments may not easily be extrapolatable to other species.
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Affiliated With Hiller, Predoc first author
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DOI 10.1093/gbe/evz238
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Created By thuem
Added Date 2019-11-04
Last Edited By thuem
Last Edited Date 2020-01-10 10:10:20.248
Library ID 7538
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