UniProt release 2016_10
Published November 2, 2016
N-acyl amino acids: a new treatment for obesity?
Mitochondria play a fundamental role in energy production. After glycolysis, glucose products are imported into the mitochondrial matrix, where they go through the citric acid cycle. The electrons produced in this process are transported from one protein complex to the next in the mitochondrial inner membrane. The final electron acceptor is molecular oxygen, which is ultimately reduced to water. During electron transport, the participating protein complexes pump protons out of the matrix space into the intermembrane space and thus create a concentration gradient. This gradient is used by ATP synthase to power the phosphorylation of ADP into ATP. However not all energy liberated from the oxidation of dietary substrates is converted into ATP. Protons can leak back to the matrix through the inner membrane independently of ATP synthase and the energy accumulated is dissipated as heat. Several proteins are known to be involved in this process, called “uncoupled respiration”. One of them, UCP1 has been most extensively studied in the context of thermogenesis mediated by brown and beige adipose tissues.
Adaptive thermogenesis does not rely exclusively upon UCP1. Adipose tissues secrete many bioactive proteins, some of which potentially play a role in the regulation of energy expenditure. Recently, Long et al. identified a protein secreted by brown and beige fat cells, PM20D1. This protein is co-expressed with UCP1 in adipocytes. When injected with PM20D1 viral expression vectors and placed on high fat diet for a period of 47 to 54 days, mice exhibited a blunted weight gain, due to a massive reduction in fat mass compared with control animals. There was no difference in food intake, nor in movement between treated and untreated animals, suggesting the activation of a thermogenic gene program in the classical brown fat (BAT), subcutaneous inguinal white fat (iWAT), or both. Interestingly, UCP1 levels were unchanged in these experiments.
In vitro, PM20D1 appeared to be a bidirectional N-acyl amino acid synthase and hydrolase, the synthase activity being lower than the hydrolase activity. In vivo, plasma levels of N-oleyl-phenylalanine (C18:1-Phe) were indeed elevated in mice injected with PM20D1 expression vector. But what is the effect of N-lipidated amino acids on cells? When treated with N-acyl amino acids, primary BAT adipocytes and differentiated iWAT cells showed increased oxygen consumption in a UCP1-independent manner, indicating respiratory uncoupling activity of these compounds. The N-acyl amino acids tested (N-arachidonyl-glycine (C20:4-Gly), C20:4-Phe, and C18:1-Phe) acted directly on mitochondria, possibly by interaction with mitochondrial transporter proteins, such as SLC25A4 and SLC25A5. Of note, SLC25A4 and SLC25A5 exhibit ADP/ATP symport activity, but are also thought to translocate protons across the inner membrane. Finally treatment of obese mice with C18:1-Leu induced weight loss through the reduction of fat mass and improved glucose tolerance tests.
In the 1930s, the mitochondrial uncoupling 2,4 dinitrophenol was used in diet pills to stimulate metabolism and promote weight loss and actually it can still be purchased on the internet for this purpose. Though quite efficient in terms of weight loss, this drug has severe side effects. It can cause an excessive rise in body temperature due to the heat produced during uncoupling. DNP overdose causes fatal hyperthermia, with body temperature rising to as high as 44oC shortly before death. Will N-acyl-amino acids become a new, this time innocuous, treatment of choice for obesity? It’s difficult to anticipate. Chronic treatment of mice with C18:1-Phe or C20:4-Gly not only increases energy expenditure, with no effects on movement, but also reduces food intake, which obviously also contributes to weight loss. However, several N-acyl-amino acids have other biological functions, besides respiratory uncoupling, and hence may have other (undesirable?) effects. Nevertheless the study of Long et al. sheds light on new endogenous mitochondrial uncouplers and new thermogenic mechanisms that are undoubtedly worth further investigation.
As of this release, PM20D1 entries have been updated and are publicly available.
Cross-references to DisGeNET
Cross-references have been added to DisGeNET, a discovery platform for the dynamical exploration of human diseases and their genes.
DisGeNET is available at http://www.disgenet.org.
The format of the explicit links is:
|Resource identifier||Gene identifier (corresponding to GeneID gene identifier)|
DR DisGeNET; 348; -.
<dbReference type="DisGeNET" id="348"/>
uniprot:P02649 rdfs:seeAlso <http://identifiers.org/ncbigene/348> . <http://identifiers.org/ncbigene/348> rdf:type up:Resource ; up:database <http://purl.uniprot.org/database/DisGeNET> .
Cross-references to OpenTargets
Cross-references have been added to OpenTargets. This Target Validation platform brings together information on the relationships between potential drug targets and diseases. The core concept is to identify evidence of an association between a target and disease from various data types.
OpenTargets is available at https://www.targetvalidation.org/.
The format of the explicit links is:
|Resource identifier||Gene identifier (corresponding to Ensembl gene identifier)|
DR OpenTargets; ENSG00000157764; -.
<dbReference type="OpenTargets" id="ENSG00000157764"/>
uniprot:P15056 rdfs:seeAlso <http://purl.uniprot.org/opentargets/ENSG00000157764> . <http://purl.uniprot.org/opentargets/ENSG00000157764> rdf:type up:Resource ; up:database <http://purl.uniprot.org/database/OpenTargets> .
Change of the cross-references to PhosphoSite
The PhosphoSite resource has changed its name to PhosphoSitePlus and we have updated our cross-references to reflect this name change.
Change of the cross-references to SMR
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DR SMR; Q00362; 4-376, 492-523.
DR SMR; Q00362; -.
<dbReference type="SMR" id="Q00362"> <property type="residue range" value="4-376, 492-523"/> </dbReference>
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We have modified the representation of our cross-references to PDB. These cross-references indicate the sequence ranges of the UniProt canonical sequence that are covered by a PDB structure when this data is available. This piece of information was provided via a reification of the cross-reference statement and each range was represented with a
chain property that had a string literal value. We have introduced a new
chainSequenceMapping property to simplify this description.
uniprot:P00750 rdfs:seeAlso <http://rdf.wwpdb.org/pdb/1A5H> . <http://rdf.wwpdb.org/pdb/1A5H> rdf:type up:Structure_Resource ; up:database <http://purl.uniprot.org/database/PDB> ; up:method up:X-Ray_Crystallography ; up:resolution "2.90"^^xsd:float . <#_5030303735300036> rdf:type rdf:Statement ; rdf:type up:Structure_Mapping_Statement ; rdf:subject uniprot:P00750 ; rdf:predicate rdfs:seeAlso ; rdf:object <http://rdf.wwpdb.org/pdb/1A5H> ; up:chain "A/B=311-562" , "C/D=298-304" .
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Changes to the controlled vocabulary of human diseases
- Arthrogryposis, Perthes disease, and upward gaze palsy
- Ataxia-pancytopenia syndrome
- Autoinflammation, panniculitis, and dermatosis syndrome
- Bone marrow failure syndrome 3
- Camptosynpolydactyly, complex
- Cardiomyopathy, familial hypertrophic 26
- Cardiomyopathy, familial restrictive 5
- Charcot-Marie-Tooth disease 2A2B
- Cholestasis, progressive familial intrahepatic, 5
- Cold-induced sweating syndrome 3
- Congenital disorder of glycosylation 1AA
- Curry-Jones syndrome
- Duane retraction syndrome 3 with or without deafness
- Encephalopathy due to defective mitochondrial and peroxisomal fission 2
- Epileptic encephalopathy, early infantile, 38
- Epileptic encephalopathy, early infantile, 40
- Familial juvenile hyperuricemic nephropathy 4
- Hermansky-Pudlak syndrome 10
- Hydrops, lactic acidosis, and sideroblastic anemia
- Hyperaldosteronism, familial, 4
- Hypermanganesemia with dystonia 2
- Intellectual developmental disorder with persistence of fetal hemoglobin
- Lethal congenital contracture syndrome 10
- Limb-girdle muscular dystrophy 2Y
- Lipid storage myopathy due to flavin adenine dinucleotide synthetase deficiency
- Macrocephaly, dysmorphic facies, and psychomotor retardation
- Meier-Gorlin syndrome 7
- Mental retardation, autosomal dominant 44
- Mental retardation, autosomal recessive 54
- Mental retardation, autosomal recessive 55
- Mental retardation, X-linked 49
- Mental retardation, X-linked 61
- MIRAGE syndrome
- Muscular dystrophy, congenital, Davignon-Chauveau type
- Myopathy, distal, 5
- Nasopharyngeal carcinoma, 3
- Nephrolithiasis, calcium oxalate
- Neutropenia, severe congenital 7, autosomal recessive
- Nevus comedonicus
- Night blindness, congenital stationary, 1H
- Okur-Chung neurodevelopmental syndrome
- Parkinson disease 19B, early-onset
- Patent ductus arteriosus 2
- Patent ductus arteriosus 3
- PEHO syndrome
- Pigmentary disorder, reticulate, with systemic manifestations, X-linked
- Polycystic kidney disease 3
- Polycystic liver disease 2
- Pontocerebellar hypoplasia 2F
- Portal hypertension, non-cirrhotic
- Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3
- Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4
- Pyle disease
- Retinitis pigmentosa 75
- Seizures, benign familial infantile, 5
- Short-rib thoracic dysplasia 15 with polydactyly
- Short-rib thoracic dysplasia 16 with or without polydactyly
- Short stature, developmental delay, and congenital heart defects
- Spastic paraplegia 77, autosomal recessive
- Spinocerebellar ataxia 43
- Spondyloepimetaphyseal dysplasia, X-linked
- Striatonigral degeneration, childhood-onset
- Tooth agenesis, selective, 8
- Cataract, juvenile, with microcornea and glucosuria -> Cataract 47
- Cerebral palsy, spastic quadriplegic 4 -> Spastic paraplegia 51, autosomal recessive
- Cerebral palsy, spastic quadriplegic 5 -> Spastic paraplegia 47, autosomal recessive
- Cerebral palsy, spastic quadriplegic 6 -> Spastic paraplegia 52, autosomal recessive
- Charcot-Marie-Tooth disease 2A2 -> Charcot-Marie-Tooth disease 2A2A
- Encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission -> Encephalopathy due to defective mitochondrial and peroxisomal fission 1
- Familial hyperaldosteronism 1 -> Hyperaldosteronism, familial, 1
- Familial hyperaldosteronism 3 -> Hyperaldosteronism, familial, 3
- Global cerebral hypomyelination -> Epileptic encephalopathy, early infantile, 39
- Hypermanganesemia with dystonia, polycythemia, and cirrhosis -> Hypermanganesemia with dystonia 1
- Mental retardation, autosomal dominant 17 -> Schuurs-Hoeijmakers syndrome
- Parkinson disease 19, juvenile-onset -> Parkinson disease 19A, juvenile-onset
- Polycystic liver disease -> Polycystic liver disease 1
- Seizures, benign familial infantile 2 -> Seizures, benign familial infantile, 2
- Seizures, benign familial infantile 3 -> Seizures, benign familial infantile, 3
- Tooth agenesis selective 1 -> Tooth agenesis, selective, 1
- Tooth agenesis selective 3 -> Tooth agenesis, selective, 3
- Tooth agenesis selective 4 -> Tooth agenesis, selective, 4
- Tooth agenesis selective 7 -> Tooth agenesis, selective, 7
- Tooth agenesis selective X-linked 1 -> Tooth agenesis, selective, X-linked, 1
- X-linked adrenal hypoplasia congenital -> Adrenal hypoplasia, congenital
Changes to the controlled vocabulary for PTMs
New term for the feature key ‘Modified residue’ (‘MOD_RES’ in the flat file):
- Hydroxylated arginine
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