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Abstract
The glycyl radical enzyme (GRE) superfamily utilizes a glycyl radical cofactor to catalyze difficult chemical reactions in a variety of anaerobic microbial metabolic pathways. Recently, a GRE, trans-4-hydroxy-L-proline (Hyp) dehydratase (HypD), was discovered that catalyzes the dehydration of Hyp to (S)-Δ1-pyrroline-5-carboxylic acid (P5C). This enzyme is abundant in the human gut microbiome and also present in prominent bacterial pathogens. However, we lack an understanding of how HypD performs its unusual chemistry. Here, we have solved the crystal structure of HypD from the pathogen Clostridioides difficile with Hyp bound in the active site. Biochemical studies have led to the identification of key catalytic residues and have provided insight into the radical mechanism of Hyp dehydration.
Highlights
The microbes that inhabit the human body, collectively referred to as the human microbiome, catalyze a diverse range of chemical reactions that can have profound impacts on human health (Sharon et al, 2014; Joice et al, 2014; Koppel et al, 2017)
We believe that glycerol binding is an artifact, it is not surprising that glycerol is able to bind given hydroxyproline dehydratase (HypD)’s high sequence similarity to glycerol dehydratase (GD)
On the basis of these previous studies and the structural insights gained in this work, we propose a possible mechanism for HypD, similar to those proposed for other glycyl radical enzyme (GRE) eliminases, that involves a direct elimination of the hydroxyl group on Hyp to generate P5C (Figure 7)
Summary
The microbes that inhabit the human body, collectively referred to as the human microbiome, catalyze a diverse range of chemical reactions that can have profound impacts on human health (Sharon et al, 2014; Joice et al, 2014; Koppel et al, 2017). The most densely populated microbial environment among human body sites is the gastrointestinal (GI) tract with an estimated 1011 bacterial cells per gram (Tropini et al, 2017; Sender et al, 2016). Due to the largely anoxic nature of the GI tract, this body site is inhabited by facultative and obligate anaerobes that perform a wide variety of challenging chemical transformations. It is clear that the gut microbiome plays a significant role in human health, the biochemical reactions governing bacterial-host homeostasis remain unclear.
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