PM20D1 explained

Peptidase M20 domain containing 1 is a circulating enzyme which in humans is encoded by the PM20D1 gene.^[1] PM20D1 regulates bioactive N-acyl amide lipids and has been implicated in obesity, type 2 diabetes, pain, and Alzheimer's disease.

Function

PM20D1 catalyzes the biosynthesis of N-fatty acyl amino acids from free fatty acids and free amino acids.^[2] Consequently PM20D1 is involved in the generation of potent bioactive lipid metabolites from two abundant cellular energy precursors.

PM20D1 is involved in energy homeostasis. In mice, PM20D1 is highly expressed and secreted into the blood by brown fat. Its expression in adipose tissues is increased following cold exposure. Genetic elevation of circulating PM20D1 in mice leads to accumulation of multiple circulating N-acyl amino acid species and a hypermetabolic phenotype. Conversely, PM20D1-KO exhibit bidirectional dysregulation of circulating N-acyl amino acids, insulin resistance, and glucose intolerance.^[3] Mechanistically, N-fatty acyl amino acids function as UCP1-independent uncouplers of mitochondrial respiration.^{[4] [5]}

PM20D1 has also been implicated in neurological diseases. PM20D1 expression is increased both in vitro and in vivo following neurotoxic insults. Forced overexpression of PM20D1 in the hippocampus results in improved learning performance in a mouse model of Alzheimer's disease whereas PM20D1 knockdown increases amyloid plaque load.^[6]

Clinical significance

In human visceral and subcutaneous adipocytes, PM20D1 is one of the most highly up-regulated genes by the anti-diabetic thiazolidinedione drug rosiglitazone, suggesting a potential role for this enzyme and/or N-fatty acyl amino acids in obesity and diabetes.^[7]

Methylation at or near the PM20D1 locus has been correlated to body mass index.^[8]

In humans, the PM20D1 locus has been associated with Alzheimer's disease.

Notes and References

1. Web site: Entrez Gene: Peptidase M20 domain containing 1 . 2016-05-13 .
2. Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, Lou J, Rao RR, Chang MR, Jedrychowski MP, Paulo JA, Gygi SP, Griffin PR, Nomura DK, Spiegelman BM . 6 . The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria . Cell . 166 . 2 . 424–435 . July 2016 . 27374330 . 4947008 . 10.1016/j.cell.2016.05.071 .
3. Long JZ, Roche AM, Berdan CA, Louie SM, Roberts AJ, Svensson KJ, Dou FY, Bateman LA, Mina AI, Deng Z, Jedrychowski MP, Lin H, Kamenecka TM, Asara JM, Griffin PR, Banks AS, Nomura DK, Spiegelman BM . 6 . N-acyl amino acid control of metabolism and nociception . Proceedings of the National Academy of Sciences of the United States of America . 115 . 29 . E6937–E6945 . July 2018 . 29967167 . 6055169 . 10.1073/pnas.1803389115 . free .
4. Keipert S, Kutschke M, Ost M, Schwarzmayr T, van Schothorst EM, Lamp D, Brachthäuser L, Hamp I, Mazibuko SE, Hartwig S, Lehr S, Graf E, Plettenburg O, Neff F, Tschöp MH, Jastroch M . 6 . Long-Term Cold Adaptation Does Not Require FGF21 or UCP1 . Cell Metabolism . 26 . 2 . 437–446.e5 . August 2017 . 28768181 . 10.1016/j.cmet.2017.07.016 . free .
5. Lin H, Long JZ, Roche AM, Svensson KJ, Dou FY, Chang MR, Strutzenberg T, Ruiz C, Cameron MD, Novick SJ, Berdan CA, Louie SM, Nomura DK, Spiegelman BM, Griffin PR, Kamenecka TM . 6 . Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration . Journal of Medicinal Chemistry . 61 . 7 . 3224–3230 . April 2018 . 29533650 . 6335027 . 10.1021/acs.jmedchem.8b00029 .
6. Sanchez-Mut JV, Heyn H, Silva BA, Dixsaut L, Garcia-Esparcia P, Vidal E, Sayols S, Glauser L, Monteagudo-Sánchez A, Perez-Tur J, Ferrer I, Monk D, Schneider B, Esteller M, Gräff J . 6 . PM20D1 is a quantitative trait locus associated with Alzheimer's disease . Nature Medicine . 24 . 5 . 598–603 . May 2018 . 29736028 . 10.1038/s41591-018-0013-y . 10261/181902 . 13663888 . free.
7. Lee MJ, Jash S, Jones JE, Puri V, Fried SK . Rosiglitazone remodels the lipid droplet and britens human visceral and subcutaneous adipocytes ex vivo . Journal of Lipid Research . 60 . 4 . 856–868 . April 2019 . 30782959 . 6446708 . 10.1194/jlr.M091173 . free .
8. Feinberg AP, Irizarry RA, Fradin D, Aryee MJ, Murakami P, Aspelund T, Eiriksdottir G, Harris TB, Launer L, Gudnason V, Fallin MD . 6 . Personalized epigenomic signatures that are stable over time and covary with body mass index . Science Translational Medicine . 2 . 49 . 49ra67 . September 2010 . 20844285 . 10.1126/scitranslmed.3001262 . 3137242 .