Bioinformatic Analysis of the Flavin-Dependent Amine Oxidase Superfamily: Adaptations for Substrate Specificity and Catalytic Diversity

JOURNAL OF MOLECULAR BIOLOGY

卷:432

Article

Tararina, Margarita A.¹  Allen, Karen N.^1,2 

[1] Boston Univ, Program Biomol Pharmacol, Sch Med, 72 East Concord St, Boston, MA 02118 USA

[2] Boston Univ, Dept Chem, 590 Commonwealth Ave, Boston, MA 02215 USA

关键词: flavoprotein;    amine oxidase;    sequence similarity network;    genome neighborhood network;    structure-function relationship;   

DOI  :  10.1016/j.jmb.2020.03.007

来源: Elsevier

【 摘 要 】

The flavin-dependent amine oxidase (FAO) superfamily consists of over 9000 nonredundant sequences represented in all domains of life. Of the thousands of members identified, only 214 have been functionally annotated to date, and 40 unique structures are represented in the Protein Data Bank. The few functionally characterized members share a catalytic mechanism involving the oxidation of an amine substrate through transfer of a hydride to the FAD cofactor, with differences observed in substrate specificities. Previous studies have focused on comparing a subset of superfamily members. Here, we present a comprehensive analysis of the FAO superfamily based on reaction mechanism and substrate recognition. Using a dataset of 9192 sequences, a sequence similarity network, and subsequently, a genome neighborhood network were constructed, organizing the superfamily into eight subgroups that accord with substrate type. Likewise, through phylogenetic analysis, the evolutionary relationship of subgroups was determined, delineating the divergence between enzymes based on organism, substrate, and mechanism. In addition, using sequences and atomic coordinates of 22 structures from the Protein Data Bank to perform sequence and structural alignments, active-site elements were identified, showing divergence from the canonical aromatic-cage residues to accommodate large substrates. These specificity determinants are held in a structural framework comprising a core domain catalyzing the oxidation of amines with an auxiliary domain for substrate recognition. Overall, analysis of the FAO superfamily reveals a modular fold with cofactor and substrate-binding domains allowing for diversity of recognition via insertion/deletions. This flexibility allows facile evolution of new activities, as shown by reinvention of function between subfamilies. (C) 2020 Elsevier Ltd. All rights reserved.

【 授权许可】

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