Peptidase M20 domain containing 1 is a circulating enzyme which in humans is encoded by the PM20D1 gene.[5] PM20D1 regulates bioactive N-acyl amide lipids and has been implicated in obesity, type 2 diabetes, pain, and Alzheimer's disease.
Function
editPM20D1 catalyzes the biosynthesis of N-fatty acyl amino acids from free fatty acids and free amino acids.[6] 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.[6] Conversely, PM20D1-KO exhibit bidirectional dysregulation of circulating N-acyl amino acids, insulin resistance, and glucose intolerance.[7] Mechanistically, N-fatty acyl amino acids function as UCP1-independent uncouplers of mitochondrial respiration.[6][8][9]
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.[10]
Clinical significance
editIn 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.[11]
Methylation at or near the PM20D1 locus has been correlated to body mass index.[12]
In humans, the PM20D1 locus has been associated with Alzheimer's disease.[10]
References
edit- ^ a b c GRCh38: Ensembl release 89: ENSG00000162877 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000042251 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: Peptidase M20 domain containing 1". Retrieved 2016-05-13.
- ^ a b c Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, et al. (July 2016). "The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria". Cell. 166 (2): 424–435. doi:10.1016/j.cell.2016.05.071. PMC 4947008. PMID 27374330.
- ^ Long JZ, Roche AM, Berdan CA, Louie SM, Roberts AJ, Svensson KJ, et al. (July 2018). "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. doi:10.1073/pnas.1803389115. PMC 6055169. PMID 29967167.
- ^ Keipert S, Kutschke M, Ost M, Schwarzmayr T, van Schothorst EM, Lamp D, et al. (August 2017). "Long-Term Cold Adaptation Does Not Require FGF21 or UCP1". Cell Metabolism. 26 (2): 437–446.e5. doi:10.1016/j.cmet.2017.07.016. PMID 28768181.
- ^ Lin H, Long JZ, Roche AM, Svensson KJ, Dou FY, Chang MR, et al. (April 2018). "Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration". Journal of Medicinal Chemistry. 61 (7): 3224–3230. doi:10.1021/acs.jmedchem.8b00029. PMC 6335027. PMID 29533650.
- ^ a b Sanchez-Mut JV, Heyn H, Silva BA, Dixsaut L, Garcia-Esparcia P, Vidal E, et al. (May 2018). "PM20D1 is a quantitative trait locus associated with Alzheimer's disease". Nature Medicine. 24 (5): 598–603. doi:10.1038/s41591-018-0013-y. hdl:10261/181902. PMID 29736028. S2CID 13663888.
- ^ Lee MJ, Jash S, Jones JE, Puri V, Fried SK (April 2019). "Rosiglitazone remodels the lipid droplet and britens human visceral and subcutaneous adipocytes ex vivo". Journal of Lipid Research. 60 (4): 856–868. doi:10.1194/jlr.M091173. PMC 6446708. PMID 30782959.
- ^ Feinberg AP, Irizarry RA, Fradin D, Aryee MJ, Murakami P, Aspelund T, et al. (September 2010). "Personalized epigenomic signatures that are stable over time and covary with body mass index". Science Translational Medicine. 2 (49): 49ra67. doi:10.1126/scitranslmed.3001262. PMC 3137242. PMID 20844285.
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