Catechol dehydroxylation is a central chemical transformation in the gut microbial metabolism of plant- and host-derived small molecules. However, the molecular basis for this transformation and its distribution among gut microorganisms are poorly understood. Here, we characterize a molybdenum-dependent enzyme from the human gut bacterium Eggerthella lenta that dehydroxylates catecholamine neurotransmitters. Our findings suggest that this activity enables E. lenta to use dopamine as an electron acceptor. We also identify candidate dehydroxylases that metabolize additional host- and plant-derived catechols. These dehydroxylases belong to a distinct group of largely uncharacterized molybdenum-dependent enzymes that likely mediate primary and secondary metabolism in multiple environments. Finally, we observe catechol dehydroxylation in the gut microbiotas of diverse mammals, confirming the presence of this chemistry in habitats beyond the human gut. These results suggest that the chemical strategies that mediate metabolism and interactions in the human gut are relevant to a broad range of species and habitats.

17Catechol dehydroxylation is a central chemical transformation in the gut microbial 18 metabolism of plant-and host-derived small molecules. However, the molecular basis for this 19 transformation and its distribution among gut microorganisms are poorly understood. Here, we 20 characterize a molybdenum-dependent enzyme from the prevalent human gut bacterium 21Eggerthella lenta that specifically dehydroxylates catecholamine neurotransmitters available in 22 the human gut. Our findings suggest that this activity enables E. lenta to use dopamine as an 23 electron acceptor under anaerobic conditions. In addition to characterizing catecholamine 24 dehydroxylation, we identify candidate molybdenum-dependent enzymes that dehydroxylate 25 additional host-and plant-derived small molecules. These gut bacterial catechol dehydroxylases 26 are specific in their substrate scope and transcriptional regulation and belong to a distinct group of 27 range of compounds that includes dietary phytochemicals, host neurotransmitters, clinically used 51 drugs, and microbial siderophores (14-16) ( Fig. 1A). Discovered over six decades ago, catechol 52 dehydroxylation is a uniquely microbial reaction that selectively replaces the para hydroxyl group 53 of the catechol with a hydrogen atom (17) (Fig. 1A). This reaction is particularly challenging due 54 to the stability of the aromatic ring system. Prominent substrates for microbial dehydroxylation 55 include the drug fostamatinib (18), the catecholamine neurotransmitters norepinephrine and 56 dopamine (19,20), and the phytochemicals ellagic acid (found in nuts and berries), caffeic acid (a 57 universal lignin precursor in plants), and catechin (present in chocolate and tea) (21-23) ( Fig. 1B). 58Dehydroxylation alters the bioactivity of the catechol compound (24, 25) and produces metabolites 59 that act both locally in the gut and systemically to influence human health and disease (18,(25)(26)(27)(28)(29)(30). 60However, the gut microbial enzymes responsible for catechol dehydroxylation have remained 61 largely unknown. 62We recently reported the discovery of a catechol dehydroxylating enzyme from the 63 prevalent human gut Actinobacterium Eggerthella lenta. This enzyme participates in an 64 interspecies gut microbial pathway that degrades the Parkinson's disease medication L-dopa by 65 catalyzing the regioselective p-dehydroxylation of dopamine to m-tyramine (29). To identify the 66 enzyme, we grew E. lenta strain A2 with and without dopamine and used RNA sequencing (RNA-67 seq) to find genes induced by dopamine. Only 15 genes were significantly upregulated in the 68 presence of dopamine, including a putative molybdenum-dependent enzyme that was induced 69 >2500 fold. Hypothesizing this gene encoded the dopamine dehydroxylase, we purified the 70 enzyme from E. lenta and confirmed its activity in vitro. Dopamine dehydroxylase (Dadh) is 71 predicted to bind bis-molybdopterin guanine nucleotide (bis-MGD), a complex metallocofactor 72 that contains a catalytically essential molybdenum atom (...

Molybdenum- and tungsten-dependent proteins catalyze essential processes in living organisms and biogeochemical cycles. Among these enzymes, members of the dimethyl sulfoxide (DMSO) reductase superfamily are considered the most diverse, facilitating a wide range of chemical transformations that can be categorized as oxygen atom installation, removal, and transfer. Importantly, DMSO reductase enzymes provide high efficiency and excellent selectivity while operating under mild conditions without conventional oxidants such as oxygen or peroxides. Despite the potential utility of these enzymes as biocatalysts, such applications have not been fully explored. In addition, the vast majority of DMSO reductase enzymes still remain uncharacterized. In this review, we describe the reactivities, proposed mechanisms, and potential synthetic applications of selected enzymes in the DMSO reductase superfamily. We also highlight emerging opportunities to discover new chemical activity and current challenges in studying and engineering proteins in the DMSO reductase superfamily. Expected final online publication date for the Annual Review of Biochemistry, Volume 91 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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