PM20D1

Last updated
PM20D1
Identifiers
Aliases PM20D1 , Cps1, peptidase M20 domain containing 1
External IDs OMIM: 617124 MGI: 2442939 HomoloGene: 65049 GeneCards: PM20D1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_152491

NM_178079
NM_001357478

RefSeq (protein)

NP_689704

NP_835180
NP_001344407

Location (UCSC) Chr 1: 205.83 – 205.85 Mb Chr 1: 131.73 – 131.75 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

Contents

Function

PM20D1 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

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. [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]

Related Research Articles

Lipid Substance of biological origin that is soluble in nonpolar solvents

In biology and biochemistry, a lipid is a macro biomolecule that is soluble in nonpolar solvents. Non-polar solvents are typically hydrocarbons used to dissolve other naturally occurring hydrocarbon lipid molecules that do not dissolve in water, including fatty acids, waxes, sterols, fat-soluble vitamins, monoglycerides, diglycerides, triglycerides, and phospholipids.

ACADM Mammalian protein found in Homo sapiens

ACADM is a gene that provides instructions for making an enzyme called acyl-coenzyme A dehydrogenase that is important for breaking down (degrading) a certain group of fats called medium-chain fatty acids.

Perilipin-1

Perilipin, also known as lipid droplet-associated protein, Perilipin 1, or PLIN, is a protein that, in humans, is encoded by the PLIN gene. The perilipins are a family of proteins that associate with the surface of lipid droplets. Phosphorylation of perilipin is essential for the mobilization of fats in adipose tissue.

ACADL Protein-coding gene in the species Homo sapiens

Acyl-CoA dehydrogenase, long chain is a protein that in humans is encoded by the ACADL gene.

FADS2

Fatty acid desaturase 2 (FADS2) is encoded by the FADS2 gene, the associated enzyme is sometimes known as FADS2 as well. Its main associated enzyme is Delta 6 desaturase (D6D) however the human enzyme been shown to also catalyze some delta-8 and delta-4 desaturases in spite of naming conventions.

ACSL5 Protein-coding gene in the species Homo sapiens

Long-chain-fatty-acid—CoA ligase 5 is an enzyme that in humans is encoded by the ACSL5 gene.

ACSL3 Protein-coding gene in the species Homo sapiens

Long-chain-fatty-acid—CoA ligase 3 is an enzyme that in humans is encoded by the ACSL3 gene.

ACOT2 Protein-coding gene in the species Homo sapiens

Acyl-CoA thioesterase 2, also known as ACOT2, is an enzyme which in humans is encoded by the ACOT2 gene.

Very long-chain acyl-CoA synthetase

Very long-chain acyl-CoA synthetase is an enzyme that in humans is encoded by the SLC27A2 gene.

ACOT7 Protein-coding gene in the species Homo sapiens

Cytosolic acyl coenzyme A thioester hydrolase is an enzyme that in humans is encoded by the ACOT7 gene.

ACOT4 Protein-coding gene in the species Homo sapiens

Acyl-coenzyme A thioesterase 4 is an enzyme that in humans is encoded by the ACOT4 gene.

ACOT11 Protein-coding gene in the species Homo sapiens

Acyl-coenzyme A thioesterase 11 also known as StAR-related lipid transfer protein 14 (STARD14) is an enzyme that in humans is encoded by the ACOT11 gene. This gene encodes a protein with acyl-CoA thioesterase activity towards medium (C12) and long-chain (C18) fatty acyl-CoA substrates which relies on its StAR-related lipid transfer domain. Expression of a similar murine protein in brown adipose tissue is induced by cold exposure and repressed by warmth. Expression of the mouse protein has been associated with obesity, with higher expression found in obesity-resistant mice compared with obesity-prone mice. Alternative splicing results in two transcript variants encoding different isoforms.

Lipid droplets, also referred to as lipid bodies, oil bodies or adiposomes, are lipid-rich cellular organelles that regulate the storage and hydrolysis of neutral lipids and are found largely in the adipose tissue. They also serve as a reservoir for cholesterol and acyl-glycerols for membrane formation and maintenance. Lipid droplets are found in all eukaryotic organisms and store a large portion of lipids in mammalian adipocytes. Initially, these lipid droplets were considered to merely serve as fat depots, but since the discovery in the 1990s of proteins in the lipid droplet coat that regulate lipid droplet dynamics and lipid metabolism, lipid droplets are seen as highly dynamic organelles that play a very important role in the regulation of intracellular lipid storage and lipid metabolism. The role of lipid droplets outside of lipid and cholesterol storage has recently begun to be elucidated and includes a close association to inflammatory responses through the synthesis and metabolism of eicosanoids and to metabolic disorders such as obesity, cancer, and atherosclerosis. In non-adipocytes, lipid droplets are known to play a role in protection from lipotoxicity by storage of fatty acids in the form of neutral triacylglycerol, which consists of three fatty acids bound to glycerol. Alternatively, fatty acids can be converted to lipid intermediates like diacylglycerol (DAG), ceramides and fatty acyl-CoAs. These lipid intermediates can impair insulin signaling, which is referred to as lipid-induced insulin resistance and lipotoxicity. Lipid droplets also serve as platforms for protein binding and degradation. Finally, lipid droplets are known to be exploited by pathogens such as the hepatitis C virus, the dengue virus and Chlamydia trachomatis among others.

FA2H

Fatty acid 2-hydroxylase is a protein that in humans is encoded by the FA2H gene.

<i>N</i>-Arachidonylglycine Chemical compound

N-Arachidonylglycine (NAGly) is a carboxylic metabolite of the endocannabinoid anandamide (AEA). Since it was first synthesized in 1996, NAGly has been a primary focus of the relatively contemporary field of lipidomics due to its wide range of signaling targets in the brain, the immune system and throughout various other bodily systems. In combination with 2‐arachidonoyl glycerol (2‐AG), NAGly has enabled the identification of a family of lipids often referred to as endocannabinoids. Recently, NAGly has been found to bind to G-protein coupled receptor 18 (GPR18), the putative abnormal cannabidiol receptor. NaGly is an endogenous inhibitor of fatty acid amide hydrolase (FAAH) and thereby increases the ethanolamide endocannabinoids AEA, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels. NaGly is found throughout the body and research on its explicit functions is ongoing.

<i>N</i>-Acylamides

N-acyl amides are a general class of endogenous fatty acid compounds characterized by a fatty acyl group linked to a primary amine metabolite by an amide bond. Broadly speaking, N-acyl amides fall into several categories: amino acid conjugates, neurotransmitter conjugates, ethanolamine conjugates, and taurine conjugates. N-acyl amides have pleiotropic signaling functions in physiology, including in cardiovascular function, metabolic homeostasis, memory, cognition, pain, motor control and others. Initial attention focused on N-acyl amides present in mammalian organisms, however recently lipid signaling systems consisting of N-acyl amides have also been found to be present in invertebrates, such as Drosophila melanogaster. N-acyl amides play important roles in many biochemical pathways involved in a variety of physiological and pathological processes, as well as the metabolic enzymes, transporters, and receptors that regulate their signaling.

ACOT13 Protein-coding gene in the species Homo sapiens

Acyl-CoA thioesterase 13 is a protein that in humans is encoded by the ACOT13 gene. This gene encodes a member of the thioesterase superfamily. In humans, the protein co-localizes with microtubules and is essential for sustained cell proliferation.

ACOT1 Protein-coding gene in the species Homo sapiens

Acyl-CoA thioesterase 1 is a protein that in humans is encoded by the ACOT1 gene.

Erythroferrone

Erythroferrone is a protein hormone encoded in humans by the ERFE gene. Erythroferrone is produced by erythroblasts, inhibits the production of hepcidin in the liver, and so increases the amount of iron available for hemoglobin synthesis. Skeletal muscle secreted ERFE has been shown to maintain systemic metabolic homeostasis.

Lipase a, lysosomal acid type

Lipase A, lysosomal acid type is a protein that in humans is encoded by the LIPA gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000162877 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000042251 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: Peptidase M20 domain containing 1" . Retrieved 2016-05-13.
  6. 1 2 3 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.
  7. 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.
  8. 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.
  9. 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.
  10. 1 2 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.
  11. 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.
  12. 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.