Metabolic Functions of the Human Gut Microbiota: the Role of Metalloenzymes Cite This: DOI: 10.1039/C8np00074c Lauren J

Natural Product Reports View Article Online REVIEW View Journal Metabolic functions of the human gut microbiota: the role of metalloenzymes Cite this: DOI: 10.1039/c8np00074c Lauren J. Rajakovich and Emily P. Balskus * Covering: up to the end of 2017 The human body is composed of an equal number of human and microbial cells. While the microbial community inhabiting the human gastrointestinal tract plays an essential role in host health, these organisms have also been connected to various diseases. Yet, the gut microbial functions that modulate host biology are not well established. In this review, we describe metabolic functions of the human gut microbiota that involve metalloenzymes. These activities enable gut microbial colonization, mediate interactions with the host, and impact human health and disease. We highlight cases in which enzyme characterization has advanced our understanding of the gut microbiota and examples that illustrate the diverse ways in which Received 14th August 2018 Creative Commons Attribution 3.0 Unported Licence. metalloenzymes facilitate both essential and unique functions of this community. Finally, we analyze Human DOI: 10.1039/c8np00074c Microbiome Project sequencing datasets to assess the distribution of a prominent family of metalloenzymes rsc.li/npr in human-associated microbial communities, guiding future enzyme characterization efforts. 1 Introduction our gut from infancy and plays a critical role in the development 2 Commensal colonization of the human gut: tness and and maintenance of healthy human physiology. It aids in adaptation developing the innate and adaptive immune systems,1,2 2.1 Glycan sulfation provides nutrients and vitamins,3 and protects against path- 4 This article is licensed under a 2.2 Glycan fucosylation ogen invasion. Counter to its vital role in normal physiology, 3 Colonization resistance to pathogenic microbes the gut microbiota has also been linked to a wide range of 4 Biosynthesis of essential nutrients human diseases.5 Unsurprisingly, many of these conditions are 4.1 Vitamin biosynthesis localized to the gastrointestinal tract, including colorectal Open Access Article. Published on 19 November 2018. Downloaded 1/21/2019 1:08:23 AM. 4.2 Queuosine biosynthesis cancer6 and inammatory bowel diseases (IBD)7 like Crohn's 5 Production of host immune-modulatory metabolites disease and ulcerative colitis. However, the gut microbiota has 6 Gut microbial metabolism linked to human disease also been connected with systemic diseases, such as obesity and 6.1 Trimethylamine production diabetes,8 and with maladies of distal organs, including 6.2 p-Cresol production neurological and cardiovascular disorders.9,10 6.3 Ammonia production The intriguing relationship between the gut microbiota and 6.4 Hydrogen sulde production its host elicits fundamental questions about the composition 7 Microbial metabolism of xenobiotics of this community in both health and disease states, the gut 8 Metalloenzyme abundance in human microbiomes microbial functions that inuence host biology, and ulti- 9 Conclusions mately, the ways that this knowledge can be leveraged to 10 Conicts of interest improve human health. Over the last decade and a half, the 11 Acknowledgements application of next-generation sequencing has signicantly 12 References advanced the eld toward addressing the rst point.11 Taxo- nomic proling of gut microbial communities has shown that only two bacterial phyla, Bacteroidetes and Firmicutes, typi- 1 Introduction cally dominate this habitat in healthy western populations.12,13 The human gastrointestinal (GI) tract harbors a unique and However, the bacteria within these two phyla that constitute complex microbial ecosystem consisting of trillions of bacteria, the community have been found to vary greatly in healthy fungi, archaea, and viruses. This microbial community inhabits populations depending on geography, age, and environmental factors.14,15 These discoveries have dispelled the concept of a core community of gut bacteria that are characteristic of Department of Chemistry and Chemical Biology, Harvard University, USA. E-mail: [email protected] a healthy person. Instead, the focus has shi ed toward de ning This journal is © The Royal Society of Chemistry 2018 Nat. Prod. Rep. View Article Online Natural Product Reports Review conserved microbial functions that promote host health or could even be direct targets for therapeutics.23,24 However, the affect disease susceptibility.16 present challenge to leverage this type of analysis or manipu- The metabolic potential of the gut microbiota greatly late gut microbial functions is that only 50% of genes from surpasses that of the host as its genetic content exceeds that of human stool metagenomes can be assigned a broad functional the human genome 150-fold.17,18 Consequently, gut microbes annotation and less than half of that 50% can be given more produce a vast set of small molecules that are oen chemically descriptive annotations.25 This gap in knowledge limits our distinct from those generated by host metabolism.19 The understanding of the metabolic functions of the gut micro- nature of these metabolites and their abundance can vary biota and the molecular basis of the diseases linked to this substantially between individuals depending on the compo- community. This vast area of unexplored biochemical space sition of their gut microbiota and dietary intake.20 In many creates a need, as well as great opportunity, for biochemists cases, metabolites produced by the host and the gut micro- and chemical biologists to contribute to this exciting eld. biota are exchanged and can be co-metabolized to generate Metalloenzymes are an important class of enzymes for all molecules that can have unique consequences in the context domains of life. In enzyme catalysis, metallocofactors enable of the human body.21 Indeed, many microbially-produced unique molecular rearrangements and transformations of metabolites have been strongly correlated with human relatively chemically inert molecules. In particular, anaerobic disease.22 Thus, the chemical output of microbial metabolism microbes oen use metalloenzymes to promote radical catal- is becoming recognized as a critical component of human ysis, which presents challenges in aerobic environments due healthanddisease.However,wecurrentlylackamolecular to the reactivity of dioxygen with organic radical intermedi- understanding of gut microbial metabolic activities. Bacteria ates.26 In the anoxic environment of the human colon, from this habitat are oen difficult to cultivate in the labora- anaerobic bacteria deploy metalloenzymes to perform many tory. In addition, bacteria of the same genus and even from the interesting metabolic functions. These metal-dependent same species can have substantially divergent metabolic transformations can enable gut microbes to access nutrients Creative Commons Attribution 3.0 Unported Licence. capabilities.Therefore,taxonomicpro ling, which at present or energy from alternative substrates or to generate molecules is limited to genus level assignments, is insufficient to provide that can have important consequences for the host. This an accurate assessment or prediction of the metabolic func- review describes unique metabolic functions of the human gut tions of the gut microbiota. microbiota that involve metalloenzymes. Rather than The identication of specic organisms, genes, and providing a comprehensive account of all extant metal- enzymes responsible for metabolic functions of interest will loenzymes employed by gut microbes for housekeeping improve our understanding of the metabolic potential of the functions, we will focus on enzymatic transformations that gut microbiota and its role in host health and disease. Meta- enable gut microbes to interact with their environment, genomic, metatranscriptomic and metaproteomic approaches pathogens, ingested compounds (dietary molecules and This article is licensed under a are currently used to prole the gut microbiota on a commu- xenobiotics), and the human host. Finally, we evaluate the nity level. Ideally, specic genes, transcripts, or proteins could prevalence and distribution of the major families of metal- be used as indicators in complex meta'omic data to predict the loenzymes across the healthy human microbiota, with the goal presence of a metabolic function and potentially serve as of inspiring further investigation into characterized and Open Access Article. Published on 19 November 2018. Downloaded 1/21/2019 1:08:23 AM. a personalized read-out of health status. Microbial enzymes Lauren Rajakovich received her Emily Balskus received her BA BS in chemistry from Wake from Williams College and her Forest University and her PhD in PhD in synthetic organic chem- biochemistry from Pennsylvania istry from Harvard University, State University. Her graduate where she worked with Eric work in the joint laboratory of J. Jacobsen. Her postdoctoral Martin Bollinger, Jr. and Cars- studies at Harvard Medical ten Krebs focused on mecha- School with Christopher T. nistic characterization of non- Walsh focused on deciphering heme diiron oxidases and oxy- the biosynthesis of cyanobacte- genases involved in microbial rial sunscreens. She began her biofuel production and organo- independent career at Harvard phosphonate metabolism. She is University in 2011 and is now currently a Helen Hay Whitney postdoctoral fellow with Emily a Professor of Chemistry and Chemical Biology. Her research Balskus at Harvard University. Her research

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