Publications

• Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration.

  Lin H., Long J.Z., Roche A.M., Svensson K.J., Dou F.Y., Chang M.R., Strutzenberg T., Ruiz C., Cameron M.D., Novick S.J., Berdan C.A., Louie S.M., Nomura D.K., Spiegelman B.M., Griffin P.R., Kamenecka T.M.

  N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure, indicating that this pathway might be useful for treating o ... >> More

  N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure, indicating that this pathway might be useful for treating obesity and associated disorders. We report the full account of the synthesis and mitochondrial uncoupling bioactivity of lipidated N-acyl amino acids and their unnatural analogues. Unsaturated fatty acid chains of medium length and neutral amino acid head groups are required for optimal uncoupling activity on mammalian cells. A class of unnatural N-acyl amino acid analogues, characterized by isoindoline-1-carboxylate head groups (37), were resistant to enzymatic degradation by PM20D1 and maintained uncoupling bioactivity in cells and in mice. << Less

  J. Med. Chem. 61:3224-3230(2018) [PubMed] [EuropePMC]

• A Plasma Protein Network Regulates PM20D1 and N-Acyl Amino Acid Bioactivity.

  Kim J.T., Jedrychowski M.P., Wei W., Fernandez D., Fischer C.R., Banik S.M., Spiegelman B.M., Long J.Z.

  N-acyl amino acids are a family of cold-inducible circulating lipids that stimulate thermogenesis. Their biosynthesis is mediated by a secreted enzyme called PM20D1. The extracellular mechanisms that regulate PM20D1 or N-acyl amino acid activity in the complex environment of blood plasma remains u ... >> More

  N-acyl amino acids are a family of cold-inducible circulating lipids that stimulate thermogenesis. Their biosynthesis is mediated by a secreted enzyme called PM20D1. The extracellular mechanisms that regulate PM20D1 or N-acyl amino acid activity in the complex environment of blood plasma remains unknown. Using quantitative proteomics, here we show that PM20D1 circulates in tight association with both low- and high-density lipoproteins. Lipoprotein particles are powerful co-activators of PM20D1 activity in vitro and N-acyl amino acid biosynthesis in vivo. We also identify serum albumin as a physiologic N-acyl amino acid carrier, which spatially segregates N-acyl amino acids away from their sites of production, confers resistance to hydrolytic degradation, and establishes an equilibrium between thermogenic "free" versus inactive "bound" fractions. These data establish lipoprotein particles as principal extracellular sites of N-acyl amino acid biosynthesis and identify a lipoprotein-albumin network that regulates the activity of a circulating thermogenic lipid family. << Less

  Cell Chem. Biol. 0:0-0(2020) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• Ablation of PM20D1 reveals N-acyl amino acid control of metabolism and nociception.

  Long J.Z., Roche A.M., Berdan C.A., Louie S.M., Roberts A.J., Svensson K.J., Dou F.Y., Bateman L.A., Mina A.I., Deng Z., Jedrychowski M.P., Lin H., Kamenecka T.M., Asara J.M., Griffin P.R., Banks A.S., Nomura D.K., Spiegelman B.M.

  <i>N</i>-acyl amino acids (NAAs) are a structurally diverse class of bioactive signaling lipids whose endogenous functions have largely remained uncharacterized. To clarify the physiologic roles of NAAs, we generated mice deficient in the circulating enzyme peptidase M20 domain-containing 1 (PM20D ... >> More

  <i>N</i>-acyl amino acids (NAAs) are a structurally diverse class of bioactive signaling lipids whose endogenous functions have largely remained uncharacterized. To clarify the physiologic roles of NAAs, we generated mice deficient in the circulating enzyme peptidase M20 domain-containing 1 (PM20D1). Global PM20D1-KO mice have dramatically reduced NAA hydrolase/synthase activities in tissues and blood with concomitant bidirectional dysregulation of endogenous NAAs. Compared with control animals, PM20D1-KO mice exhibit a variety of metabolic and pain phenotypes, including insulin resistance, altered body temperature in cold, and antinociceptive behaviors. Guided by these phenotypes, we identify <i>N</i>-oleoyl-glutamine (C18:1-Gln) as a key PM20D1-regulated NAA. In addition to its mitochondrial uncoupling bioactivity, C18:1-Gln also antagonizes certain members of the transient receptor potential (TRP) calcium channels including TRPV1. Direct administration of C18:1-Gln to mice is sufficient to recapitulate a subset of phenotypes observed in PM20D1-KO animals. These data demonstrate that PM20D1 is a dominant enzymatic regulator of NAA levels in vivo and elucidate physiologic functions for NAA signaling in metabolism and nociception. << Less

  Proc. Natl. Acad. Sci. U.S.A. 115:E6937-E6945(2018) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• The secreted enzyme PM20D1 regulates lipidated amino acid uncouplers of mitochondria.

  Long J.Z., Svensson K.J., Bateman L.A., Lin H., Kamenecka T., Lokurkar I.A., Lou J., Rao R.R., Chang M.R., Jedrychowski M.P., Paulo J.A., Gygi S.P., Griffin P.R., Nomura D.K., Spiegelman B.M.

  Brown and beige adipocytes are specialized cells that express uncoupling protein 1 (UCP1) and dissipate chemical energy as heat. These cells likely possess alternative UCP1-independent thermogenic mechanisms. Here, we identify a secreted enzyme, peptidase M20 domain containing 1 (PM20D1), that is ... >> More

  Brown and beige adipocytes are specialized cells that express uncoupling protein 1 (UCP1) and dissipate chemical energy as heat. These cells likely possess alternative UCP1-independent thermogenic mechanisms. Here, we identify a secreted enzyme, peptidase M20 domain containing 1 (PM20D1), that is enriched in UCP1(+) versus UCP1(-) adipocytes. We demonstrate that PM20D1 is a bidirectional enzyme in vitro, catalyzing both the condensation of fatty acids and amino acids to generate N-acyl amino acids and also the reverse hydrolytic reaction. N-acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. Mice with increased circulating PM20D1 have augmented respiration and increased N-acyl amino acids in blood. Lastly, administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure. These data identify an enzymatic node and a family of metabolites that regulate energy homeostasis. This pathway might be useful for treating obesity and associated disorders. << Less

  Cell 166:424-435(2016) [PubMed] [EuropePMC]

  This publication is cited by 13 other entries.