AOAH

Homo sapiens (Human)

Acyloxyacyl hydrolase

NA

NA

Removes the secondary (acyloxyacyl-linked) fatty acyl chains from the lipid A region of bacterial lipopolysaccharides. By breaking down LPS, terminates the host response to bacterial infection and prevents prolonged and damaging inflammatory responses (By similarity). In peritoneal macrophages, seems to be important for recovery from a state of immune tolerance following infection by Gram-negative bacteria (By similarity).

Major depressive disorder (MDD) [MIM:608516]: A common psychiatric disorder. It is a complex trait characterized by one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes. A major depressive episode is characterized by at least 2 weeks during which there is a new onset or clear worsening of either depressed mood or loss of interest or pleasure in nearly all activities. Four additional symptoms must also be present including changes in appetite, weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation, plans, or attempts. The episode must be accompanied by distress or impairment in social, occupational, or other important areas of functioning. {ECO:0000269|PubMed:15229186}. Disease susceptibility is associated with variants affecting the gene represented in this entry.

NA

Q15700

EC 3.1.1.77

3D-structure; Alternative splicing; Calcium; Cytoplasmic vesicle; Direct protein sequencing; Disulfide bond; Glycoprotein; Hydrolase; Lipid metabolism; Metal-binding; Proteomics identification; Reference proteome; Secreted; Signal; Zymogen

C

47779.7

420

0.1

43.45

7.72

2.1

-7.78

IRAK1

Homo sapiens (Human)

Interleukin-1 receptor-associated kinase 1; IRAK-1; IRAK

Protein kinase superfamily, TKL Ser/Thr protein kinase family, Pelle subfamily

Kinase

Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3. Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens.

Anemia, non-spherocytic hemolytic, due to G6PD deficiency (NSHA) [MIM:300908]: A disease characterized by G6PD deficiency, acute hemolytic anemia, fatigue, back pain, and jaundice. In most patients, the disease is triggered by an exogenous agent, such as some drugs, food, or infection. Increased unconjugated bilirubin, lactate dehydrogenase, and reticulocytosis are markers of the disorder. Although G6PD deficiency can be life-threatening, most patients are asymptomatic throughout their life. {ECO:0000269|PubMed:12524354, ECO:0000269|PubMed:1303180, ECO:0000269|PubMed:1303182, ECO:0000269|PubMed:1536798, ECO:0000269|PubMed:1611091, ECO:0000269|PubMed:1889820, ECO:0000269|PubMed:1945893, ECO:0000269|PubMed:20007901, ECO:0000269|PubMed:26479991, ECO:0000269|PubMed:2836867, ECO:0000269|PubMed:2912069, ECO:0000269|PubMed:30988594, ECO:0000269|PubMed:38066190, ECO:0000269|PubMed:7858267, ECO:0000269|PubMed:7959695, ECO:0000269|PubMed:8193373, ECO:0000269|PubMed:8490627, ECO:0000269|PubMed:8533762, ECO:0000269|PubMed:8733135, ECO:0000269|PubMed:9452072}. The disease is caused by variants affecting the gene represented in this entry. Deficiency of G6PD is associated with hemolytic anemia in two different situations. First, in areas in which malaria has been endemic, G6PD-deficiency alleles have reached high frequencies (1% to 50%) and deficient individuals, though essentially asymptomatic in the steady state, have a high risk of acute hemolytic attacks. Secondly, sporadic cases of G6PD deficiency occur at a very low frequencies, and they usually present a more severe phenotype. Several types of NSHA are recognized. Class-I variants are associated with severe NSHA; class-II have an activity <10% of normal; class-III have an activity of 10% to 60% of normal; class-IV have near normal activity.

DB12010

Q15306; Q92985; Q99836; Q96FA3; Q9HAT8; Q8N2H9-2; Q13526; Q86WV6; P58753; Q9Y4K3; Q8VCW4; Q5D1E7

EC 2.7.11.1

3D-structure; Alternative splicing; ATP-binding; Cytoplasm; Direct protein sequencing; Host-virus interaction; Immunity; Innate immunity; Isopeptide bond; Kinase; Lipid droplet; Magnesium; Nucleotide-binding; Nucleus; Phosphoprotein; Proteomics identification; Reference proteome; Serine/threonine-protein kinase; Transferase; Ubl conjugation

A

33681.4

301

0.09

39.86

8.6

5.09

-7.77

mtnN

Escherichia coli (strain K12)

NA

pfs;b0159;yadA;JW0155;mtn

PNP/UDP phosphorylase family, MtnN subfamily

hydrolase / hydrolase inhibitor

Adenosylhomocysteine nucleosidase activity.Identical protein binding.Methylthioadenosine nucleosidase activity.

Pigmentary disorder, reticulate, with systemic manifestations, X-linked (PDR) [MIM:301220]: An X-linked recessive disorder characterized by recurrent infections and sterile inflammation in various organs. Diffuse skin hyperpigmentation with a distinctive reticulate pattern is universally evident by early childhood. This is later followed in many patients by hypohidrosis, corneal inflammation and scarring, enterocolitis that resembles inflammatory bowel disease, and recurrent urethral strictures. Melanin and amyloid deposition is present in the dermis. Affected males also have a characteristic facies with frontally upswept hair and flared eyebrows. Female carriers have only restricted pigmentary changes along Blaschko's lines. {ECO:0000269|PubMed:27019227}. The disease is caused by variants affecting the gene represented in this entry. XLPDR is caused by a recurrent intronic mutation that results in missplicing and reduced POLA1 expression. This leads to a decrease in cytosolic RNA:DNA hybrids and constitutive activation of type I interferon responses, but has no effect on cell replication. {ECO:0000269|PubMed:27019227}.; DISEASE: Van Esch-O'Driscoll syndrome (VEODS) [MIM:301030]: An X-linked recessive syndrome characterized by different degrees of intellectual disability, moderate to severe short stature, microcephaly, hypogonadism, and variable congenital malformations. {ECO:0000269|PubMed:31006512}. The disease is caused by variants affecting the gene represented in this entry.

DB02158; DB08606; DB02933; DB00173; DB02281

P0AF12

3.2.2.9

3D-structure; Amino-acid biosynthesis; Hydrolase; Methionine biosynthesis; Reference proteome

A

24353.7

232

0.05

22.1

5.09

-9.9

-7.77

benC

Acinetobacter baylyi (strain ATCC 33305 / BD413 / ADP1)

NA

ACIAD1438

Bacterial ring-hydroxylating dioxygenase ferredoxin reductase family

Oxidoreductase

2 iron, 2 sulfur cluster binding.Electron carrier activity.Ferredoxin-NAD+ reductase activity.Metal ion binding.

Adenine phosphoribosyltransferase deficiency (APRTD) [MIM:614723]: An enzymatic deficiency that can lead to urolithiasis and renal failure. Patients have 2,8-dihydroxyadenine (DHA) urinary stones. {ECO:0000269|PubMed:11243733, ECO:0000269|PubMed:1353080, ECO:0000269|PubMed:15571218, ECO:0000269|PubMed:1746557, ECO:0000269|PubMed:21635362, ECO:0000269|PubMed:3343350, ECO:0000269|PubMed:3680503, ECO:0000269|PubMed:7915931}. The disease is caused by variants affecting the gene represented in this entry.

DB03147

NA

1.18.1.3

2Fe-2S; 3D-structure; Aromatic hydrocarbons catabolism; FAD; Flavoprotein; Iron; Iron-sulfur; Metal-binding; NAD; Oxidoreductase

A,B

37496.7

337

0.1

47.02

4.75

-18.87

-7.77

TAT

Homo sapiens (Human)

NA

NA

Class-I pyridoxal-phosphate-dependent aminotransferase family

Transferase

Amino acid binding.L-phenylalanine:2-oxoglutarate aminotransferase activity.L-tyrosine:2-oxoglutarate aminotransferase activity.Pyridoxal phosphate binding.

Tyrosinemia 2 (TYRSN2) [MIM:276600]: An inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, and oculocutaneous manifestations. Typical features include palmoplantar keratosis, painful corneal ulcers, and intellectual disability. {ECO:0000269|PubMed:1357662}. The disease is caused by variants affecting the gene represented in this entry.

DB00142; DB00120; DB00114; DB00135

P15104; P28799; P28799-2; P17735; Q05086; Q05086-3

2.6.1.5

3D-structure; Acetylation; Aminotransferase; Disease variant; Intellectual disability; Palmoplantar keratoderma; Phenylalanine catabolism; Phosphoprotein; Proteomics identification; Pyridoxal phosphate; Reference proteome; Transferase; Tyrosine catabolism

A,B

42209.5

380

0.08

51.79

5.29

-10.66

-7.77

RIDA

Homo sapiens (Human)

NA

HRSP12

RutC family

Translation

Deaminase activity.Endoribonuclease activity, producing 3'-phosphomonoesters.Long-chain fatty acid binding.Platinum binding.Protein homodimerization activity.RNA binding.Transition metal ion binding.Xenon atom binding.

Congenital bile acid synthesis defect 2 (CBAS2) [MIM:235555]: A condition characterized by jaundice, intrahepatic cholestasis and hepatic failure. Patients with this liver disease show absence or low levels of chenodeoxycholic acid and cholic acid in plasma and urine. {ECO:0000269|PubMed:12970144, ECO:0000269|PubMed:15030995, ECO:0000269|PubMed:19175828, ECO:0000269|PubMed:20522910}. The disease is caused by variants affecting the gene represented in this entry.

NA

Q8N9N5-2

3.5.99.10

3D-structure; Acetylation; Cytoplasm; Direct protein sequencing; Hydrolase; Lipid metabolism; Mitochondrion; Nucleus; Peroxisome; Phosphoprotein; Proteomics identification; Reference proteome; RNA-binding

A,B,C,D,E,F,G,H,I

42624.3

404

0.07

36.76

8.99

5.46

-7.77

ACC1

Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)

NA

MTR7;YNR016C;N3175;ABP2;FAS3

NA

NA

Carries out three functions: biotin carboxyl carrier protein, biotin carboxylase and carboxyltransferase. Involved in the synthesis of very-long-chain fatty acid synthesis which is required to maintain a functional nuclear envelope. Required for acylation and vacuolar membrane association of VAC8 which is necessary to maintain a normal morphology of the vacuole. {ECO:0000269|PubMed:10757783, ECO:0000269|PubMed:12730220, ECO:0000269|PubMed:6103540, ECO:0000269|PubMed:6108218, ECO:0000269|PubMed:8943372}."

A chromosomal aberration involving NFKB2 is found in a case of B-cell non Hodgkin lymphoma (B-NHL). Translocation t(10;14)(q24;q32) with IGHA1. The resulting oncogene is also called Lyt-10C alpha variant.; DISEASE: A chromosomal aberration involving NFKB2 is found in a cutaneous T-cell leukemia (C-TCL) cell line. This rearrangement produces the p80HT gene which codes for a truncated 80 kDa protein (p80HT).; DISEASE: In B-cell leukemia (B-CLL) cell line, LB40 and EB308, can be found after heterogeneous chromosomal aberrations, such as internal deletions.; DISEASE: Immunodeficiency, common variable, 10 (CVID10) [MIM:615577]: A primary immunodeficiency characterized by childhood-onset of recurrent infections, hypogammaglobulinemia, and decreased numbers of memory and marginal zone B-cells. Some patients may develop autoimmune features and have circulating autoantibodies. An unusual feature is central adrenal insufficiency. {ECO:0000269|PubMed:24140114, ECO:0000269|PubMed:25524009}. The disease is caused by variants affecting the gene represented in this entry.

NA

Q00955

6.3.4.14; 6.4.1.2

3D-structure; Acetylation; ATP-binding; Biotin; Cytoplasm; Direct protein sequencing; Endoplasmic reticulum; Fatty acid biosynthesis; Fatty acid metabolism; Ligase; Lipid biosynthesis; Lipid metabolism; Manganese; Membrane; Metal-binding; Multifunctional enzyme; Nucleotide-binding; Phosphoprotein; Reference proteome

B,C

145619

1328

0.1

30.31

5.32

-26.79

-7.76

PPARA

Homo sapiens (Human)

Peroxisome proliferater-activated receptor alpha; PPARalpha; PPAR-alpha; PPAR; Nuclear receptor subfamily 1 group C member 1; NR1C1

Nuclear hormone receptor family, NR1 subfamily

Nuclear hormone receptor

Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2. Ligand-activated transcription factor.

Combined oxidative phosphorylation deficiency 33 (COXPD33) [MIM:617713]: An autosomal recessive disorder caused by multiple mitochondrial respiratory chain defects and impaired mitochondrial energy metabolism. Clinical manifestations are highly variable. Affected infants present with cardiomyopathy accompanied by multisystemic features involving liver, kidney, and brain. Death in infancy is observed in some patients. Children and adults present with myopathy and progressive external ophthalmoplegia. {ECO:0000269|PubMed:28942965}. The disease is caused by variants affecting the gene represented in this entry.

DB08915; DB00132; DB01118; DB04557; DB01393; DB04519; DB05416; DB09064; DB09006; DB00636; DB09213; DB03756; DB05187; DB06521; DB01039; DB13873; DB00573; DB13961; DB02266; DB01241; DB07215; DB01050; DB00159; DB07724; DB00328; DB12007; DB03017; DB12961; DB06510; DB08231; DB11605; DB01890; DB04224; DB11133; DB03796; DB02746; DB01708; DB06533; DB04971; DB02709; DB00412; DB09422; DB03193; DB06536; DB00197; DB00313

P02768-3; P55212; P45973; P06307; Q3L8U1-3; G5E9A7; P22607; P62993; Q14957; P06396; P42858; Q8WXH2; P13473-2; O75376; Q13133; A0A6Q8PF08; P54725; P62826; Q7Z699; P37173; P55072; P55055-1; Q13133

NA

3D-structure; Activator; Alternative splicing; Biological rhythms; DNA-binding; Lipid-binding; Metal-binding; Nucleus; Proteomics identification; Receptor; Reference proteome; Transcription; Transcription regulation; Ubl conjugation; Zinc; Zinc-finger

A

29322.1

258

0.09

35.53

6.09

-3.57

-7.76

ACE2

Homo sapiens (Human)

Processed angiotensinconverting enzyme 2; Metalloprotease MPROT15; Angiotensinconverting enzyme homolog; Angiotensinconverting enzyme 2; ACErelated carboxypeptidase; ACEH; ACE2

Peptidase M2 family

Peptidase

Carboxypeptidase which converts angiotensin I to angiotensin 1-9, a peptide of unknown function, and angiotensin II to angiotensin 1-7, a vasodilator. Also able to hydrolyze apelin- 13 and dynorphin-13 with high efficiency. May be an important regulator of heart function. In case of human coronaviruses SARS and HCoV-NL63 infections, serve as functional receptor for the spike glycoprotein of both coronaviruses.

Cornelia de Lange syndrome 5 (CDLS5) [MIM:300882]: A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. It is characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies. {ECO:0000269|PubMed:22885700, ECO:0000269|PubMed:22889856}. The disease is caused by variants affecting the gene represented in this entry.

DB09019; DB00608; DB01611; DB15643; DB05203

Q9BYF1; PRO_0000032457 [P01019]; PRO_0000032458 [P01019]; Q96CW1; PRO_0000000092 [P05067]; Q9H2X3; PRO_0000417390 [Q01523]; Q14416; P11021; P05556; O60341; PRO_0000006688 [P01042]; O14745; PRO_0000019524 [P30990]; Q5T2W1; P35247; Q9Y566; Q695T7; Q96L92; O15393; P08670; P52293; A0A6B9WHD3; A0A6G6A1M4; A0A6M3G9R1; P0DTC2; PRO_0000449647 [P0DTC2]; P59594; PRO_0000037209 [P59594]; Q5GDB5; Q6Q1S2

EC 3.4.17.23

3D-structure; Alternative splicing; Carboxypeptidase; Cell membrane; Cell projection; Chloride; Cytoplasm; Direct protein sequencing; Disulfide bond; Glycoprotein; Host cell receptor for virus entry; Host-virus interaction; Hydrolase; Isopeptide bond; Membrane; Metal-binding; Metalloprotease; Phosphoprotein; Protease; Proteomics identification; Receptor; Reference proteome; Secreted; Signal; Transmembrane; Transmembrane helix; Ubl conjugation; Zinc

A

69085.2

597

0.13

42.1

5.01

-27.11

-7.77

GLTP

Homo sapiens (Human)

NA

NA

GLTP family

Lipid transport

Glycolipid binding.Glycolipid transporter activity.Identical protein binding.Intermembrane lipid transfer activity.Lipid binding.

Brugada syndrome 7 (BRGDA7) [MIM:613120]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. {ECO:0000269|PubMed:20031595}. The gene represented in this entry may be involved in disease pathogenesis.; DISEASE: Atrial fibrillation, familial, 16 (ATFB16) [MIM:613120]: A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:20558140, ECO:0000269|PubMed:21051419}. The disease is caused by variants affecting the gene represented in this entry.

DB03600; DB04465; DB03017; DB03203

Q96DZ9; Q9NZD2

NA

3D-structure; Acetylation; Cytoplasm; Lipid transport; Proteomics identification; Reference proteome; Repeat; Transport

A

23534.1

206

0.11

36.45

7.08

0.1

-7.77

USP14

Homo sapiens (Human)

Ubiquitin-specific-processing protease 14; Ubiquitin thioesterase 14; TGT; Deubiquitinating enzyme 14

Peptidase C19 family, USP14/UBP6 subfamily

Peptidase

Ensures the regeneration of ubiquitin at the proteasome. Is a reversibly associated subunit of the proteasome and a large fraction of proteasome-free protein exists within the cell. Required for the degradation of the chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis. Serves also as a physiological inhibitor of endoplasmic reticulum-associated degradation (ERAD) under the non-stressed condition by inhibiting the degradation of unfolded endoplasmic reticulum proteins via interaction with ERN1. Indispensable for synaptic development and function at neuromuscular junctions (NMJs). Plays a role in the innate immune defense against viruses by stabilizing the viral DNA sensor CGAS and thus inhibiting its autophagic degradation. Proteasome-associated deubiquitinase which releases ubiquitin from the proteasome targeted ubiquitinated proteins.

Hypophosphatemic rickets, autosomal dominant (ADHR) [MIM:193100]: A disease characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D3 (calcitriol) levels. Patients frequently present with bone pain, rickets, and tooth abscesses. {ECO:0000269|PubMed:11062477, ECO:0000269|PubMed:11409890, ECO:0000269|PubMed:16638743}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Tumoral calcinosis, hyperphosphatemic, familial, 2 (HFTC2) [MIM:617993]: A form of hyperphosphatemic tumoral calcinosis, a rare autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Some patients have recurrent, transient, painful swellings of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis and absence of skin involvement. {ECO:0000269|PubMed:15590700, ECO:0000269|PubMed:16030159, ECO:0000269|PubMed:16151858, ECO:0000269|PubMed:24680727}. The disease is caused by variants affecting the gene represented in this entry.

DB12695

Q08209

EC 3.4.19.12

3D-structure; Acetylation; Alternative splicing; Cell membrane; Cytoplasm; Hydrolase; Immunity; Innate immunity; Membrane; Phosphoprotein; Protease; Proteasome; Proteomics identification; Reference proteome; Thiol protease; Ubl conjugation pathway

A

38476.7

335

0.1

61.05

5.6

-4.84

-7.76

EPHX2

Homo sapiens (Human)

Bifunctional epoxide hydrolase 2

AB hydrolase superfamily, Epoxide hydrolase family

Ether bond hydrolase

Bifunctional enzyme. The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides. Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides (By similarity). Also determines steady-state levels of physiological mediators. The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid and 12-phosphonooxy-octadec-9E-enoic acid.

Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages. {ECO:0000269|PubMed:17332249}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Noonan syndrome 6 (NS6) [MIM:613224]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. {ECO:0000269|PubMed:19966803}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: RAS-associated autoimmune leukoproliferative disorder (RALD) [MIM:614470]: A disorder of apoptosis, characterized by chronic accumulation of non-malignant lymphocytes, defective lymphocyte apoptosis, and an increased risk for the development of hematologic malignancies. {ECO:0000269|PubMed:17517660}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Melanocytic nevus syndrome, congenital (CMNS) [MIM:137550]: A syndrome characterized by congenital pigmentary skin lesions which can occur at any site and can cover most of the body surface. These lesions may or may not be hairy. Congenital melanocytic nevi are associated with neuromelanosis (the presence of melanin-producing cells within the brain parenchyma or leptomeninges). Less commonly they are associated with malignant melanoma in childhood, both in the skin and the central nervous system. CMNS patients also tend to have a characteristic facial appearance, including wide or prominent forehead, periorbital fullness, small short nose with narrow nasal bridge, round face, full cheeks, prominent premaxilla, and everted lower lip. {ECO:0000269|PubMed:18633438, ECO:0000269|PubMed:23392294}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Melanosis, neurocutaneous (NCMS) [MIM:249400]: A rare congenital disease characterized by the presence of giant or multiple melanocytic nevi on the skin, foci of melanin-producing cells within the brain parenchyma, and infiltration of leptomeninges by abnormal melanin deposits. Neurologic abnormalities include seizures, hydrocephalus, arachnoid cysts, tumors, and syringomyelia. Some patients may develop malignant melanoma. {ECO:0000269|PubMed:23392294}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Keratinocytic non-epidermolytic nevus (KNEN) [MIM:162900]: Epidermal nevi of the common, non-organoid and non-epidermolytic type are benign skin lesions and may vary in their extent from a single (usually linear) lesion to widespread and systematized involvement. They may be present at birth or develop early during childhood. {ECO:0000269|PubMed:22499344}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Thyroid cancer, non-medullary, 2 (NMTC2) [MIM:188470]: A form of non-medullary thyroid cancer (NMTC), a cancer characterized by tumors originating from the thyroid follicular cells. NMTCs represent approximately 95% of all cases of thyroid cancer and are classified into papillary, follicular, Hurthle cell, and anaplastic neoplasms. {ECO:0000269|PubMed:12727991}. Disease susceptibility is associated with variants affecting the gene represented in this entry.

DB08257; DB08258; DB08259; DB06345; DB12610; DB08256; DB02029; DB04213; DB03677

NA

NA

3D-structure; Acetylation; Alternative splicing; Aromatic hydrocarbons catabolism; Cytoplasm; Detoxification; Direct protein sequencing; Hydrolase; Lipid metabolism; Lipoprotein; Magnesium; Metal-binding; Multifunctional enzyme; Peroxisome; Phosphoprotein; Proteomics identification; Reference proteome

A

61744.9

547

0.09

43.97

5.81

-7.76

-7.77

WNK3

Homo sapiens (Human)

Serine/threonine-protein kinase WNK3; Protein kinase with no lysine 3; Protein kinase lysine-deficient 3; KIAA1566

Protein kinase superfamily, Ser/Thr protein kinase family, WNK subfamily

NA

Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively. Phosphorylates WNK4. Regulates the phosphorylation of SLC12A1 and SLC12A2. Increases Ca(2+) influx mediated by TRPV5 and TRPV6 by enhancing their membrane expression level via a kinase-dependent pathway. Inhibits the activity of KCNJ1 by decreasing its expression at the cell membrane in a non-catalytic manner.

Prieto syndrome (PRS) [MIM:309610]: An X-linked recessive disorder characterized by impaired intellectual development, developmental delay, autism spectrum disorder, variable epilepsy, craniofacial dysmorphism, and structural brain abnormalities including polymicrogyria and cerebral atrophy. {ECO:0000269|PubMed:35678782}. The disease is caused by variants affecting the gene represented in this entry.

NA

P42574; P52954; Q04864-2

EC 2.7.11.1

3D-structure; Alternative splicing; ATP-binding; Cytoplasm; Disease variant; Intellectual disability; Kinase; Nucleotide-binding; Phosphoprotein; Proteomics identification; Reference proteome; Serine/threonine-protein kinase; Transferase; Ubl conjugation

A

30818.4

269

0.1

41.03

6.27

-2.07

-7.77

Bact nadD

Escherichia coli (strain K12)

nadD of Escherichia coli (strain K12); Nicotinate mononucleotide adenylyltransferase of Escherichia coli (strain K12); NaMN adenylyltransferase of Escherichia coli (strain K12); Deamido-NAD(+)Nicotina

NadD family

Kinase

Catalyzes the reversible adenylation of nicotinate mononucleotide (namn) to nicotinic acid adenine dinucleotide (naad).

Asthma-related traits 5 (ASRT5) [MIM:611064]: Asthma-related traits include clinical symptoms of asthma, such as coughing, wheezing, dyspnea, bronchial hyperresponsiveness as assessed by methacholine challenge test, serum IgE levels, atopy and atopic dermatitis. {ECO:0000269|PubMed:17503328}. Disease susceptibility is associated with variants affecting the gene represented in this entry.

NA

NA

EC 2.7.7.18

3D-structure; ATP-binding; NAD; Nucleotide-binding; Nucleotidyltransferase; Pyridine nucleotide biosynthesis; Reference proteome; Transferase

A

24527.6

213

0.09

48.92

5.46

-7.78

-7.76

BBOX1

Homo sapiens (Human)

NA

BBH;BBOX

Gamma-BBH/TMLD family

Oxidoreductase

Gamma-butyrobetaine dioxygenase activity.Identical protein binding.Iron ion binding.Zinc ion binding.

Neurodevelopmental disorder with poor language and loss of hand skills (NDPLHS) [MIM:617903]: An autosomal dominant disorder characterized by psychomotor developmental stagnation or regression. NDPLHS manifest in the first years of life as loss of purposeful hand movements, loss of language, and intellectual disability. {ECO:0000269|PubMed:26740508, ECO:0000269|PubMed:28856709, ECO:0000269|PubMed:29369404}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Developmental and epileptic encephalopathy 59 (DEE59) [MIM:617904]: A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE59 is an autosomal dominant condition characterized by onset of refractory seizures in early infancy. {ECO:0000269|PubMed:28856709, ECO:0000269|PubMed:29100083, ECO:0000269|PubMed:29369404}. The disease is caused by variants affecting the gene represented in this entry.

DB00126

O75936; A0MZ66-7

1.14.11.1

3D-structure; Carnitine biosynthesis; Cytoplasm; Dioxygenase; Iron; Metal-binding; Oxidoreductase; Phosphoprotein; Proteomics identification; Reference proteome; Zinc

A

31642.5

275

0.12

35.68

6.33

-2.46

-7.75

CNR1

Homo sapiens (Human)

Cannabinoid CB1 receptor; CNR; CB-R; CANN6

G-protein coupled receptor 1 family

GPCR rhodopsin

Mediates many cannabinoid-induced effects, acting, among others, on food intake, memory loss, gastrointestinal motility, catalepsy, ambulatory activity, anxiety, chronic pain. Signaling typically involves reduction in cyclic AMP. In the hypothalamus, may have a dual effect on mitochondrial respiration depending upon the agonist dose and possibly upon the cell type. Increases respiration at low doses, while decreases respiration at high doses. At high doses, CNR1 signal transduction involves G-protein alpha-i protein activation and subsequent inhibition of mitochondrial soluble adenylate cyclase, decrease in cyclic AMP concentration, inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system, including NDUFS2. In the hypothalamus, inhibits leptin-induced reactive oxygen species (ROS) formation and mediates cannabinoid-induced increase in SREBF1 and FASN gene expression. In response to cannabinoids, drives the release of orexigenic beta-endorphin, but not that of melanocyte-stimulating hormone alpha/alpha-MSH, from hypothalamic POMC neurons, hence promoting food intake. In the hippocampus, regulates cellular respiration and energy production in response to cannabinoids. Involved in cannabinoid-dependent depolarization-induced suppression of inhibition (DSI), a process in which depolarization of CA1 postsynaptic pyramidal neurons mobilizes eCBs, which retrogradely activate presynaptic CB1 receptors, transiently decreasing GABAergic inhibitory neurotransmission. Also reduces excitatory synaptic transmission. In superior cervical ganglions and cerebral vascular smooth muscle cells, inhibits voltage-gated Ca(2+) channels in a constitutive, as well as agonist-dependent manner. In cerebral vascular smooth muscle cells, cannabinoid-induced inhibition of voltage-gated Ca(2+) channels leads to vasodilation and decreased vascular tone. Induces leptin production in adipocytes and reduces LRP2-mediated leptin clearance in the kidney, hence participating in hyperleptinemia. In adipose tissue, CNR1 signaling leads to increased expression of SREBF1, ACACA and FASN genes. In the liver, activation by endocannabinoids leads to increased de novo lipogenesis and reduced fatty acid catabolism, associated with increased expression of SREBF1/SREBP-1, GCK, ACACA, ACACB and FASN genes. May also affect de novo cholesterol synthesis and HDL-cholesteryl ether uptake. Peripherally modulates energy metabolism. In high carbohydrate diet-induced obesity, may decrease the expression of mitochondrial dihydrolipoyl dehydrogenase/DLD in striated muscles, as well as that of selected glucose/ pyruvate metabolic enzymes, hence affecting energy expenditure through mitochondrial metabolism. In response to cannabinoid anandamide, elicits a proinflammatory response in macrophages, which involves NLRP3 inflammasome activation and IL1B and IL18 secretion. In macrophages infiltrating pancreatic islets, this process may participate in the progression of type-2 diabetes and associated loss of pancreatic beta-cells. G-protein coupled receptor for endogenous cannabinoids (eCBs), including N-arachidonoylethanolamide (also called anandamide or AEA) and 2-arachidonoylglycerol (2-AG), as well as phytocannabinoids, such as delta(9)-tetrahydrocannabinol (THC).

Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:18177726}. The protein represented in this entry may be involved in disease pathogenesis. May contribute to the development of diet-induced obesity and several obesity-associated features, such as dyslipidemia and liver steatosis, regulating peripheral lipogenesis, energy expenditure and feeding behavior. CNR1 inverse agonists have been shown to reduce body weight and improve metabolic abnormalities in obese subjects, although adverse neuropsychiatric effects, including anxiety, irritability, and depressed mood, halted their therapeutic development (PubMed:18177726). In obese mice, peripherally restricted CNR1 inverse agonists have been shown to normalize metabolic abnormalities, including insulin resistance and fatty liver, and to reverse leptin resistance. {ECO:0000269|PubMed:18177726}.; DISEASE: Dysfunction of the endogenous cannabinoid system including CNR1 has been implicated in the pathogenesis of a number of central nervous system disorders, including Huntington disease, Parkinson disease, and Alzheimer disease (PubMed:32549916). In post-mortem brains from Huntington disease patients, a progressive CNR1 loss has been observed in the caudate nucleus, putamen, and substantia nigra pars reticulata, and altered expression and abnormal endocannabinoid levels precede motor symptoms in a disease mouse model (PubMed:10828533, PubMed:19524019, PubMed:8255419). In Parkinson disease, low CNR1 expression in mid-superior frontal gyrus and mid-cingulate cortex has been associated with poor mind, poor executive functioning and poor episode memory, while patients with more severe visuospatial dysfunction showed decreased receptor availability in the precuneus, mid-cingulate, supplementary motor cortex, inferior orbitofrontal gyrus and thalamus (PubMed:31342135). In an animal model for Alzheimer disease, CNR1 heterozygous deletion has been associated with decreased levels of postsynaptic density protein 95 (DLG4/PSD95) and accelerated memory impairment, suggesting synaptic dysfunction and a crucial role for CNR1 in the progression of disease symptoms (PubMed:10828533, PubMed:19524019, PubMed:30096288, PubMed:31342135, PubMed:8255419). {ECO:0000269|PubMed:10828533, ECO:0000269|PubMed:19524019, ECO:0000269|PubMed:30096288, ECO:0000269|PubMed:31342135, ECO:0000269|PubMed:32549916, ECO:0000269|PubMed:8255419}.

DB05750; DB09061; DB00470; DB14009; DB00486; DB14011; DB11745; DB09288; DB02955; DB06155; DB05077; DB11755; DB05201

P29274; P21554

NA

3D-structure; Alternative splicing; Cell membrane; Cell projection; G-protein coupled receptor; Glycoprotein; Lipoprotein; Membrane; Mitochondrion; Mitochondrion outer membrane; Neurodegeneration; Obesity; Palmitate; Phosphoprotein; Proteomics identification; Receptor; Reference proteome; Synapse; Transducer; Transmembrane; Transmembrane helix

A

32070.3

282

0.13

40.15

9.16

9.36

-7.74

MAP2K1

Homo sapiens (Human)

NA

PRKMK1;MEK1

Protein kinase superfamily, STE Ser/Thr protein kinase family, MAP kinase kinase subfamily

Transferase

ATP binding.MAP kinase kinase activity.Protein C-terminus binding.Protein kinase activity.Protein N-terminus binding.Protein serine/threonine/tyrosine kinase activity.Protein serine/threonine kinase activator activity.Protein serine/threonine kinase activity.Protein tyrosine kinase activity.Signal transducer, downstream of receptor, with protein tyrosine phosphatase activity.

Cardiofaciocutaneous syndrome 3 (CFC3) [MIM:615279]: A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and intellectual disability. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. Distinctive features of CFC3 include macrostomia and horizontal shape of palpebral fissures. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:18042262}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Melorheostosis, isolated (MEL) [MIM:155950]: A sclerosing bone disorder characterized by hyperostosis of the cortex of tubular bones, frequently involving one limb. The lesions may be accompanied by abnormalities of adjacent soft tissue, joint contractures, sclerodermatous skin lesions, muscle atrophy, or hemangioma. {ECO:0000269|PubMed:29643386}. The disease is caused by variants affecting the gene represented in this entry.

DB06892; DB07046; DB08208; DB03115; DB11967; DB06616; DB05239; DB02152; DB07101; DB08130; DB14904; DB11689; DB08911

Q8N9N5; Q8N9N5-2; Q9NR09; P15056; Q9Y297; O15519-1; P28482; P27361; Q13526; Q9H8W4; P04049; Q8WWU5-7; Q86Y07; Q86Y07-1; P46937

2.7.12.2

3D-structure; Acetylation; Alternative splicing; ATP-binding; Cardiomyopathy; Cytoplasm; Cytoskeleton; Direct protein sequencing; Disease variant; Ectodermal dysplasia; Intellectual disability; Kinase; Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Proteomics identification; Reference proteome; Serine/threonine-protein kinase; Transferase; Tyrosine-protein kinase

A

34949.2

312

0.07

45.3

5.96

-4.47

-7.75

TEK

Homo sapiens (Human)

hTIE2; VMCM1; VMCM; Tyrosine-protein kinase receptor TIE-2; Tyrosine-protein kinase receptor TEK; Tyrosine kinase with Ig and EGF homology domains-2; Tunica interna endothelial cell kinase; TIE2; P140

Protein kinase superfamily, Tyr protein kinase family, Tie subfamily

Kinase

Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1. Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence.

Dominantly inherited venous malformations (VMCM) [MIM:600195]: An error of vascular morphogenesis characterized by dilated, serpiginous channels. {ECO:0000269|PubMed:10369874, ECO:0000269|PubMed:19079259, ECO:0000269|PubMed:19888299, ECO:0000269|PubMed:8980225}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Somatic mutations of TEK are associated with solitary and multiple sporadic venous malformations. {ECO:0000269|PubMed:19079259}.; DISEASE: May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.; DISEASE: Glaucoma 3, primary congenital, E (GLC3E) [MIM:617272]: An autosomal dominant form of primary congenital glaucoma (PCG). PCG is characterized by marked increase of intraocular pressure at birth or early childhood, large ocular globes (buphthalmos) and corneal edema. It results from developmental defects of the trabecular meshwork and anterior chamber angle of the eye that prevent adequate drainage of aqueous humor. {ECO:0000269|PubMed:27270174}. The disease is caused by variants affecting the gene represented in this entry.

DB00415; DB12010; DB08221; DB08901; DB08896; DB14840; DB11800; DB05294

Q15389; O15123; O15123-1; Q16678; Q05209; P23467; P08575; Q12913; Q15262; Q16827

EC 2.7.10.1

3D-structure; Alternative splicing; Angiogenesis; ATP-binding; Cell junction; Cell membrane; Cytoplasm; Cytoskeleton; Direct protein sequencing; Disease variant; Disulfide bond; EGF-like domain; Glaucoma; Glycoprotein; Immunoglobulin domain; Kinase; Membrane; Nucleotide-binding; Phosphoprotein; Proteomics identification; Receptor; Reference proteome; Repeat; Secreted; Signal; Transferase; Transmembrane; Transmembrane helix; Tyrosine-protein kinase; Ubl conjugation

A

34965.9

310

0.11

43.57

8.39

3.42

-7.75

dmg

Arthrobacter globiformis

NA

NA

GcvT family

Oxidoreductase

Dimethylglycine oxidase activity.Nucleotide binding.

Curry-Jones syndrome (CRJS) [MIM:601707]: A multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. {ECO:0000269|PubMed:24859340, ECO:0000269|PubMed:27236920}. The disease is caused by variants affecting the gene represented in this entry. 8 individuals have been identified with the disease-causing mutation Phe-412 and all were mosaic. The mutation could not be reliably detected in blood, greatest success rates were obtained with affected tissues obtained by invasive procedures. It is thought that the mutation has arisen postzygotically early during embryonic development (PubMed:27236920). This mutation has also been identified in ameloblastoma, medulloblastoma, meningioma, and basal cell carcinoma, and has been reported as the oncogenic driver in some of these tumors (PubMed:24859340). {ECO:0000269|PubMed:24859340, ECO:0000269|PubMed:27236920}.

DB03256; DB03147

NA

1.5.3.10

3D-structure; Direct protein sequencing; FAD; Flavoprotein; Nucleotide-binding; Oxidoreductase

A

45912.2

427

0.07

43.46

4.83

-20.69

-7.75

EPAS1

Homo sapiens (Human)

bHLHe73; PASD2; PAS domain-containing protein 2; Member of PAS protein 2; MOP2; Hypoxia-inducible factor 2-alpha; HLF; HIF2A; HIF2-alpha; HIF-2-alpha; HIF-1-alpha-like factor; Endothelial PAS domain-c

NA

NA

Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters. Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBBP and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD. Transcription factor involved in the induction of oxygen regulated genes.

Erythrocytosis, familial, 4 (ECYT4) [MIM:611783]: An autosomal dominant disorder characterized by elevated serum hemoglobin and hematocrit, and normal platelet and leukocyte counts. {ECO:0000269|PubMed:18184961, ECO:0000269|PubMed:18378852, ECO:0000269|PubMed:19208626, ECO:0000269|PubMed:22367913}. The disease is caused by variants affecting the gene represented in this entry.

DB15463; DB12255

P27540; Q96RK4; O00327-8; Q8WYA1-3; Q9GZT9; P60228; O60573; P09467; P61244; Q9BWF3-1; P08047; Q9Y2K6; P40818

NA

3D-structure; Activator; Angiogenesis; Congenital erythrocytosis; Developmental protein; Differentiation; Disease variant; DNA-binding; Host-virus interaction; Hydroxylation; Nucleus; Phosphoprotein; Proteomics identification; Reference proteome; Repeat; Transcription; Transcription regulation; Ubl conjugation

A

12249.8

106

0.11

40.77

5.25

-5.82

-7.75