We study bioactive metabolite pathways that control mammalian metabolism and physiology

Despite the fundamental role of signaling metabolites in mammalian physiology, significant portions of bioactive metabolite space remain entirely unexplored. Our unique and multidisciplinary approach combines synthetic chemistry, biochemistry, mass spectrometry, and genetics to chart this unmapped biochemical space. Our goal is to discover new signaling metabolites and the enzymes, transporters, and receptors that regulate their signaling. In recent years, our discoveries include a circulating PM20D1/N-acyl amino acid pathway in blood and a MAGL-controlled endocannabinoid pathway in the brain. Ultimately, we hope to translate these findings into pharmacologically tractable opportunities (e.g., enzyme inhibitors, transporter antagonists, or receptor modulators) for therapeutic intervention in cardiometabolic disease.

Below, we outline our general strategy to identify new bioactive metabolite pathways along with specific examples of projects we are actively pursuing.


 
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bioactive metabolite discovery

Nearly one third of all mammalian enzymes remain uncharacterized. A subset of the unannotated metabolic enzymes might regulate heretofore unknown signaling metabolites. Our strategy is to combine untargeted metabolomics platforms with human genetics and classical enzymology approaches to annotate uncharacterized enzymes and the signaling metabolites that they regulate. These enzyme-metabolite networks are then a starting point for perturbing cellular and organismal physiology.

 
 
 
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Receptors and proteins that mediate metabolite signaling

Bioactive metabolites often ligand and engage proteins to regulate cellular metabolism and organismal physiology. Using chemical proteomic, biochemical purification, and genome-wide screening approaches, we seek to identify the transporters and receptors that regulate the magnitude and duration of metabolite signaling. These targets provide genetic opportunities to perturb bioactive metabolite pathways in vitro and in vivo.

 
 
 
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organismal METABOLISM AND physiology

The mechanistic studies outlined above are complemented by genetic mouse models to understand how bioactive metabolite signaling affects organismal physiology. Our approach is to create genetically modified mice in which metabolite signaling pathways are perturbed. We then comprehensively characterize their phenotypes under basal and stressed conditions.

 
 

 
 
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Learn more about our projects

 
 

Uncharacterized enzymes from human genome-wide association studies

Human genome-wide association studies (GWAS) have identified metabolic enzymes linked to cardiometabolic traits. In many of these cases, such enzymes remain uncharacterized with respect to their endogenous physiologic substrates, products, and mechanism by which they regulate metabolic health. Using metabolomics, mouse genetics, and synthetic chemistry, we wish to annotate the biochemical and physiologic functions of uncharacterized enzymes identified from GWAS studies, with the hope that pharmacological targeting of their enzymatic activity may lead to new therapeutic opportunities in the treatment of metabolic disease.

Endogenous metabolite uncouplers that generate heat during fever

Fever, the heat generating response that accompanies infection, is surprisingly poorly characterized at a molecular level. Specifically, the precise chemical and biochemical genesis of heat during fever is not known. We hypothesize that endogenous metabolite uncouplers are responsible for heat generation under hyperthermic conditions. To identify such bioactive metabolites, we propose to take an untargeted metabolomics approach to identify common small molecules upregulated under hypermetabolic conditions in mice.

The signaling and physiology of amino acid-conjugated metabolites

Amino acids are abundant metabolites that serve as building blocks for proteins. Remarkably, amino acids can also be conjugated to other metabolites, including fatty acids, lactate, and acetate. The function of such N-conjugated amino acid metabolites is not precisely known but we suspect they may have interesting signaling functions in physiology. We have recently found a family of enzymes that serve as biochemical regulators for these amino acid conjugated metabolites, and wish to use this information as a handle for investigating the signaling bioactivities of these metabolites in cells and in vivo.

Metabolic diversification of neurotransmitter structure and function

Neurotransmitters, including serotonin, dopamines, and GABA are small molecules that regulate a wide range of physiology, including central nervous system control of energy homeostasis. While the biosynthesis of these neurotransmitters is well characterized, their metabolic fates remain more mysterious. For instance, nearly all neurotransmitters have been reported to be derivatized by N-fatty acylation. These "N-lipo" neurotransmitters have been detected in endogenous tissues yet their biochemical and physiologic functions remain unknown. To understand the in vivo actions of neurotransmitter derivatives, we hope use a biochemical approach to purify new enzymes that degrade these amidated metabolites. Ultimately, we wish to understand the biochemistry and physiology of mice lacking such enzymes.

Proteins required for chemical uncoupling

A class of small molecules called "chemical uncouplers" can promote proton leak in mitochondria and cause increases in respiration. Examples of chemical uncouplers include synthetic compounds (e.g., FCCP) as well as those that are endogenous consituents of mammalian tissues (e.g., N-acyl amino acids). However, precisely how these compounds promote a proton leak activity is unknown. Using genome-wide screening approaches, we hope to find proteins that mediate the action of chemical uncouplers. Such proteins may represent novel lipid receptors that participate in bioenergetics and mitochondrial function more generally.