We study the biochemical pathways that control mammalian metabolism and physiology

Mammalian metabolism is the fundamental process in which chemical bond energy in nutrients is converted into cellular energy and heat. Metabolism affects nearly every aspect of organismal physiology and homeostasis, ranging from the maintenance of energy levels during fasting to the regulation of body temperature. Dysfunction of metabolic homeostasis contributes to some of the most pressing medical problems of our generation, including obesity, type 2 diabetes, cardiovascular disease, neurodegeneration, and certain cancers.

Metabolic pathways represent critical axes of mammalian metabolism. These biochemical networks regulate chemical energy units, metabolic intermediates, and bioactive signaling metabolites. Despite our extensive knowledge of primary metabolic pathways, large regions of biochemical space still remain uncharted. Our laboratory focuses on this unmapped biochemistry with the goal of identifying new metabolic pathways and small molecules that regulate metabolism and physiology. To achieve these goals, we use a multidisciplinary approach that combines classical biochemistry, mass spectrometry, organic chemistry, and mouse genetics. Our research spans three overlapping, but distinct areas: 1) discovery of new metabolic pathways, 2) identification of genetically-encoded factors that control metabolite signaling, and 3) development of animal models for characterizing the role of metabolic pathways in physiology and disease.

Because metabolic pathways often represent unique opportunities for pharmacological intervention, in the long-term we wish to translate our discoveries into therapeutics that make a difference for human health.


 
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Metabolic pathway discovery

Despite the fundamental roles of metabolic pathways in regulating energy homeostasis, large portions of biochemical space remain entirely unexplored. Our strategy is to combine untargeted metabolomics platforms with genetic approaches and classical enzymology to concurrently annotate new metabolites and the enzymes that regulate their biosynthesis or degradation. These enzyme-metabolite networks are then a starting point for perturbing cellular and organismal physiology.

 
 
 
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GENETIC CONTROL OF Metabolite SIGNALING

Bioactive metabolites do not act alone: their signaling is tightly regulated by a collection of genetically encoded components, including extracellular and cytosolic carriers, membrane exporters and importers, biosynthetic and degradative enzymes, and cell surface or intracellular receptors. Using chemical, proteomic, biochemical, and genetic approaches, we seek to identify the protein factors that control 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 physiology

Metabolic pathways play critical roles in organismal physiology. Their dysregulation can lead to metabolic disorders including obesity, type 2 diabetes, cardiovascular disease, or non-alcoholic fatty liver disease. To interrogate the function of these pathways in vivo, we create genetically modified mice with perturbed biochemical pathways. We then comprehensively characterize their phenotypes under basal and energy-stressed conditions.

 
 

 
 
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Learn more about our projects

 
 

N-acyl amino acids in metabolic homeostasis

Amino acids and fatty acids, two fundamental energy units, can be enzymatically conjugated to generate a family of metabolites called N-acyl amino acids. We discovered that N-acyl amino acids are endogenously present in the circulation and function to stimulate mitochondrial respiration. Administration of N-acyl amino acids to mice increases energy expenditure, reduces adiposity, and improves glucose homeostasis. We are interested in understanding more about the physiologic functions and endogenous regulation of this previously enigmatic branch of bioactive lipid signaling.

Structure and function of the mammalian M20 peptidases

We have recently de-orphanized PM20D1 (peptidase M20 domain containing 1) as a bidirectional synthase and hydrolase of N-acyl amino acids. Genetic ablation of PM20D1 leads to dysregulated N-acyl amino acid levels and perturbed metabolic homeostasis, establishing PM20D1 as the principal mammalian enzymatic regulator of N-acyl amino acid signaling. Using basic biochemical and mechanistic studies of PM20D1 as a starting point, our goal is to comprehensively characterize the functions of all five of the mammalian M20 family members. Our motivation derives from genetic associations that link each of the M20 peptidase family members to human metabolic disease.

Mitochondrial proteins that mediate proton leak

N-acyl amino acids stimulate mitochondrial respiration by promoting proton leak across the inner mitochondrial membrane. These endogenous metabolites therefore mimic the action of synthetic small molecule chemical uncouplers such as dinitrophenol. However, the specific mechanism by which N-acyl amino acids promote proton movement across such an impermeant biological membrane remains unknown. Using biochemical as well as genome-wide screening approaches, we hope to find proteins that mediate the action of N-acyl amino acids. Such proteins may represent novel receptors that participate in mitochondrial bioenergetics. Their discovery could enable target-driven approaches for pharmacologically augmenting mitochondrial respiration.

Human disease-linked enzymes

Human genome-wide association studies (GWAS) have identified metabolic enzymes linked to cardiometabolic traits. However, in many of these cases the precise biochemical pathways regulated by these disease-associated enzymes remain unknown, limiting our mechanistic knowledge of how these biochemical nodes are associated with human disease. By mining publicly available GWAS studies we have recently identified an uncharacterized class of oxidation/reduction enzymes that regulate metabolic tissue function in people. We are studying their biochemical and physiologic functions with the hypotheses that these enzymes may be regulating new bioactive steroids.