The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria.
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PM20D1 is a bidirectional enzyme catalyzing both N-acyl amino acid biosynthesis and hydrolysis.
"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."
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N-acyl amino acids directly bind mitochondria and function as UCP1-independent uncouplers.
"N-acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration."
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Mice with increased circulating PM20D1 have augmented respiration and increased energy expenditure.
"Mice with increased circulating PM20D1 have augmented respiration and increased N-acyl amino acids in blood."
Large-scale proteomics and phosphoproteomics of urinary exosomes.
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniPathway vocabulary mapping.
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
Combined Automated Annotation using Multiple IEA Methods.
PM20D1 transforms oleoyl-phe from oleate and phe
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PM20D1 catalyzes the reversible condensation of L-phenylalanine and oleate to form N-oleoyl-phenylalanine.
"Extracellular PM20D1 (N-fatty-acyl-amino acid synthase/hydrolase PM20D1) catalyzes the reversible condensation of L-phenylalanine (L-phe) and oleate ((9Z)-octadecenoate) to form oleoyl-phe (N-(9Z-octadecenoyl)-L-phenylalanine) and water."
PM20D1 hydrolyzes oleoyl-phe
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PM20D1 hydrolyzes N-oleoyl-phenylalanine to yield phenylalanine and oleate.
"Extracellular PM20D1 (N-fatty-acyl-amino acid synthase/hydrolase PM20D1) catalyzes the reversible hydrolysis of oleoyl-phe (N-(9Z-octadecenoyl)-L-phenylalanine) to form L-phenylalanine (L-phe) and oleate ((9Z)-octadecenoate)."
Deep research on PM20D1 functional characterization
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PM20D1 has completely abandoned peptidase activity despite M20 family membership.
"PM20D1 has completely abandoned its ancestral peptide-cleaving function. Instead, it evolved into a bidirectional enzyme that synthesizes and hydrolyzes N-acyl amino acids."
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PM20D1 lacks a direct yeast ortholog; its function represents mammalian-specific innovation.
"PM20D1 appears to lack a direct yeast ortholog. While yeast contains M20A subfamily members like CPS1 (Gly-Xaa carboxypeptidase), the specialized function of PM20D1 in N-fatty acyl amino acid metabolism represents a mammalian-specific innovation potentially related to the evolution of thermogenic adipose tissue."
Comprehensive PM20D1 functional research
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PM20D1 circulates in tight association with LDL and HDL lipoproteins which co-activate its activity.
"PM20D1 does not circulate as a free enzyme but rather associates with lipoprotein particles. The tight association with both LDL and HDL positions PM20D1 in a lipid-rich microenvironment that facilitates access to fatty acid substrates and enhances its enzymatic activity."
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PM20D1 can synthesize N-arachidonoyl dopamine (NADA) which inhibits alpha-synuclein aggregation.
"PM20D1 catalyzes the conversion of dopamine to N-arachidonoyl dopamine (NADA), which then interacts with alpha-synuclein and inhibits its aggregation."
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PM20D1-knockout mice exhibit anti-nociceptive behaviors due to elevated N-oleoyl-glutamine antagonizing TRPV1/TRPA1.
"PM20D1-knockout mice exhibit robust anti-nociceptive behaviors in inflammatory pain models. This phenotype was linked to N-oleoyl-glutamine (C18:1-Gln), which antagonizes certain members of the TRP family of calcium channels, including TRPV1 and TRPA1."
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FAAH functions as an intracellular N-acyl amino acid synthase/hydrolase complementing extracellular PM20D1.
"While PM20D1 regulates circulating N-acyl amino acid levels, FAAH controls intracellular pools of these lipids, creating a division of labor between extracellular and intracellular compartments."
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PM20D1 represents one of the most striking examples of enzymatic neofunctionalization in evolution.
"Despite belonging to the 2.5-billion-year-old M20 metallopeptidase family, PM20D1 has completely abandoned its ancestral peptide-cleaving function."
Comprehensive PM20D1 research report
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Under assay conditions, PM20D1 exhibits higher hydrolase than synthase conversion.
"Under assay conditions, PM20D1 exhibited markedly higher hydrolase conversion (~94%) than synthase conversion (~1.2%), highlighting strong hydrolase activity and more selective synthetic activity."
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PM20D1 is secreted from brown adipose tissue, liver, kidney, and intestine.
"Endogenous secretion from brown adipose tissue (BAT), liver, kidney, and intestine has been detected; adipocytes secrete PM20D1 into circulation."