pelA

Niveispirillum irakense (Azospirillum irakense)

NA

NA

NA

Lyase

Lyase activity.

A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. {ECO:0000269|PubMed:15938644}.; DISEASE: A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. {ECO:0000269|PubMed:12112524, ECO:0000269|PubMed:16161041}.; DISEASE: A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. {ECO:0000269|PubMed:12112524}.; DISEASE: Neuroblastoma 3 (NBLST3) [MIM:613014]: A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system. {ECO:0000269|PubMed:18724359, ECO:0000269|PubMed:18923523, ECO:0000269|PubMed:18923525, ECO:0000269|PubMed:21242967, ECO:0000269|PubMed:22932897}. Disease susceptibility is associated with variants affecting the gene represented in this entry.; DISEASE: The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth. {ECO:0000269|PubMed:15908427}.; DISEASE: A chromosomal aberration involving ALK is found in one subject with colorectal cancer. Translocation t(2;2)(p23.1;p23.3). A 5 million base pair tandem duplication generates an in-frame WDCP-ALK gene fusion. {ECO:0000269|PubMed:22327622}.; DISEASE: A chromosomal aberration involving ALK has been identified in a subset of patients with non-small-cell lung carcinoma. This aberration leads to the production of a fusion protein between the N-terminus of EML4 et the C-terminus of ALK. It is unclear whether the fusion protein is caused by a simple inversion within 2p (inv(2)(p21p23)) or whether the chromosome translocation involving 2p is more complex. When tested in a heterologous system, the fusion protein EML4-ALK possesses transforming activity that is dependent on ALK catalytic activity, possibly due to spontaneous dimerization mediated by the EML4 moiety, leading to ALK kinase activation. {ECO:0000269|PubMed:17625570}.

NA

NA

NA

3D-structure; Lyase; Signal

A

41907.5

384

0.08

43.72

6.11

-3.46

-5.55

KDM2A

Homo sapiens (Human)

FBXL11; FBL7; F-box/LRR-repeat protein 11; F-box protein Lilina; F-box protein FBL7; F-box and leucine-rich repeat protein 11; CXXC8; CXXC-type zinc finger protein 8; [Histone-H3]-lysine-36 demethylas

JHDM1 histone demethylase family

NA

Histone demethylase that specifically demethylates 'Lys-36' of histone H3, thereby playing a central role in histone code. Preferentially demethylates dimethylated H3 'Lys-36' residue while it has weak or no activity for mono- and tri-methylated H3 'Lys-36'. May also recognize and bind to some phosphorylated proteins and promote their ubiquitination and degradation. Required to maintain the heterochromatic state. Associates with centromeres and represses transcription of small non-coding RNAs that are encoded by the clusters of satellite repeats at the centromere. Required to sustain centromeric integrity and genomic stability, particularly during mitosis. Regulates circadian gene expression by repressing the transcriptional activator activity of CLOCK-ARNTL/BMAL1 heterodimer and RORA in a catalytically-independent manner.

Pseudovaginal perineoscrotal hypospadias (PPSH) [MIM:264600]: A form of male pseudohermaphroditism in which 46,XY males show ambiguous genitalia at birth, including perineal hypospadias and a blind perineal pouch, and develop masculinization at puberty. The name of the disorder stems from the finding of a blind-ending perineal opening resembling a vagina and a severely hypospadiac penis with the urethra opening onto the perineum. {ECO:0000269|PubMed:10718838, ECO:0000269|PubMed:10898110, ECO:0000269|PubMed:10999800, ECO:0000269|PubMed:12843198, ECO:0000269|PubMed:15064320, ECO:0000269|PubMed:1522235, ECO:0000269|PubMed:15528927, ECO:0000269|PubMed:15770495, ECO:0000269|PubMed:16098368, ECO:0000269|PubMed:16181229, ECO:0000269|PubMed:7554313, ECO:0000269|PubMed:8626825, ECO:0000269|PubMed:8768837, ECO:0000269|PubMed:9208814, ECO:0000269|PubMed:9745434, ECO:0000269|PubMed:9843052}. The disease is caused by variants affecting the gene represented in this entry.

NA

Q04206; P63208

EC 1.14.11.27

3D-structure; ADP-ribosylation; Alternative splicing; Biological rhythms; Chromatin regulator; Chromosome; Dioxygenase; DNA-binding; Iron; Isopeptide bond; Leucine-rich repeat; Metal-binding; Nucleus; Oxidoreductase; Phosphoprotein; Proteomics identification; Reference proteome; Repeat; Repressor; Transcription; Transcription regulation; Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger

A

45337.4

386

0.12

31.19

5.5

-12.12

-5.55

NT5E

Homo sapiens (Human)

NT5; CD73 antigen; 5'-nucleotidase; 5'-NT

5'-nucleotidase family

Phosphoric monoester hydrolase

Exhibits AMP-, NAD-, and NMN-nucleosidase activities. Hydrolyzes extracellular nucleotides into membrane permeable nucleosides.

Calcification of joints and arteries (CALJA) [MIM:211800]: A condition characterized by adult-onset calcification of the lower extremity arteries, including the iliac, femoral and tibial arteries, and hand and foot capsule joints. Age of onset has been reported as early as the second decade of life, usually involving intense joint pain or calcification in the hands. {ECO:0000269|PubMed:21288095, ECO:0000269|PubMed:24887587}. The disease is caused by variants affecting the gene represented in this entry.

DB00987; DB00806

Q9Y225-2; Q8WWF5

EC 3.1.3.5

3D-structure; Alternative splicing; Cell membrane; Direct protein sequencing; Disease variant; Disulfide bond; Glycoprotein; GPI-anchor; Hydrolase; Lipoprotein; Membrane; Metal-binding; Nucleotide-binding; Proteomics identification; Reference proteome; Signal; Zinc

A

24417.6

219

0.09

40.43

5.49

-5.75

-5.54

PON1

Homo sapiens (Human)

NA

PON

Paraoxonase family

Hydrolase

Acyl-L-homoserine-lactone lactonohydrolase activity.Aryldialkylphosphatase activity.Arylesterase activity.Calcium ion binding.Phospholipid binding.Protein homodimerization activity.

Microvascular complications of diabetes 5 (MVCD5) [MIM:612633]: Pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. Disease susceptibility is associated with variants affecting the gene represented in this entry. Homozygosity for the Leu-55 allele is strongly associated with the development of retinal disease in diabetic patients.

DB01327; DB09130; DB01395; DB14598; DB14600; DB14596; DB00218; DB01085; DB01593; DB14487; DB14533; DB14548

NA

3.1.1.2; 3.1.1.81; 3.1.8.1

3D-structure; Calcium; Direct protein sequencing; Disulfide bond; Glycoprotein; HDL; Hydrolase; Metal-binding; Proteomics identification; Reference proteome; Secreted; Signal

A

37232.8

332

0.11

35.09

5.06

-17.08

-5.53

HDAC8

Homo sapiens (Human)

Histone deacetylase-8; HDACL1; HD8; CDA07

Histone deacetylase family, HD type 1 subfamily

Carbon-nitrogen hydrolase

Gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin. May play a role in smooth muscle cell contractility. Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).

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.

DB07350; DB02565; DB07586; DB12565; DB05015; DB08168; DB01262; DB11841; DB14490; DB14491; DB14488; DB14501; DB14489; DB12645; DB01592; DB02917; DB06603; DB06819; DB03766; DB12847; DB06176; DB04297; DB00313; DB02546; DB01593; DB14487; DB14533; DB14548

NA

EC 3.5.1.98

3D-structure; Alternative splicing; Chromatin regulator; Chromosome; Cytoplasm; Disease variant; Hydrolase; Intellectual disability; Metal-binding; Nucleus; Obesity; Phosphoprotein; Proteomics identification; Reference proteome; Repressor; Transcription; Transcription regulation

A,B

39018.4

351

0.11

38.57

6.06

-5.26

-5.53

UCHL1

Homo sapiens (Human)

Ubiquitin thiolesterase L1; Ubiquitin carboxyl-terminal hydrolase isozyme L1; Ubiquitin carboxy-terminal hydrolase L1; UCH-L1; PGP9.5; PGP 9.5; Neuron cytoplasmic protein 9.5

Peptidase C12 family

Peptidase

Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. Also binds to free monoubiquitin and may prevent its degradation in lysosomes. The homodimer may have ATP-independent ubiquitin ligase activity.

Parkinson disease 5 (PARK5) [MIM:613643]: A complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (resting tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia. {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:9774100}. Disease susceptibility is associated with variants affecting the gene represented in this entry.; DISEASE: Spastic paraplegia 79A, autosomal dominant, with ataxia (SPG79A) [MIM:620221]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG79A is a slowly progressive form characterized by late-onset spastic ataxia, neuropathy, and often optic atrophy. {ECO:0000269|PubMed:35986737}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Spastic paraplegia 79B, autosomal recessive (SPG79B) [MIM:615491]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG79B is characterized by childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfunction, and spasticity with upper motor neuron dysfunction. {ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:28007905}. The disease is caused by variants affecting the gene represented in this entry.

DB12695

P63010-2; P05067; P05067-2; Q8N6T3-3; P18847; Q9H1Y0; O15392; Q8WUW1; P83916; P11802; Q00535; Q9UNS2; Q92905; P00533; O60739; Q8TC29; Q9UI08-2; Q8WVV9-3; Q14164; Q6DN90-2; Q96JM7-2; P13473-2; Q9BYZ2; O95777; A4FUJ8; Q15843; O15381-5; Q9BR81; Q13113; P62826; Q8TAI7; Q9ULX5; Q15554-4; Q9NYB0; P04637; Q9Y4K3; P19474; Q9BSL1; Q7KZS0; P61086; Q9UK80; Q86WB0-2

EC 3.4.19.12

3D-structure; Cytoplasm; Direct protein sequencing; Disease variant; Endoplasmic reticulum; Glycoprotein; Hereditary spastic paraplegia; Hydrolase; Lipoprotein; Membrane; Neurodegeneration; Oxidation; Parkinson disease; Parkinsonism; Phosphoprotein; Prenylation; Protease; Proteomics identification; Reference proteome; Thiol protease; Ubl conjugation pathway

A,B

33389.8

298

0.07

38.69

5.51

-7.88

-5.53

KDM7A

Homo sapiens (Human)

Lysine-specific demethylase 7; KIAA1718; KDM7; JmjC domain-containing histone demethylation protein 1D; JHDM1D

JHDM1 histone demethylase family, JHDM1D subfamily

NA

Histone demethylase required for brain development. Specifically demethylates dimethylated 'Lys-9' and 'Lys-27' (H3K9me2 and H3K27me2, respectively) of histone H3 and monomethylated histone H4 'Lys-20' residue (H4K20Me1), thereby playing a central role in histone code. Specifically binds trimethylated 'Lys-4' of histone H3 (H3K4me3), affecting histone demethylase specificity: in presence of H3K4me3, it has no demethylase activity toward H3K9me2, while it has high activity toward H3K27me2. Demethylates H3K9me2 in absence of H3K4me3. Has activity toward H4K20Me1 only when nucleosome is used as a substrate and when not histone octamer is used as substrate.

MUC1/CA 15-3 is used as a serological clinical marker of breast cancer to monitor response to breast cancer treatment and disease recurrence (PubMed:20816948). Decreased levels over time may be indicative of a positive response to treatment. Conversely, increased levels may indicate disease progression. At an early stage disease, only 21% of patients exhibit high MUC1/CA 15-3 levels, that is why CA 15-3 is not a useful screening test. Most antibodies target the highly immunodominant core peptide domain of 20 amino acid (APDTRPAPGSTAPPAHGVTS) tandem repeats. Some antibodies recognize glycosylated epitopes. {ECO:0000269|PubMed:20816948}.; DISEASE: Tubulointerstitial kidney disease, autosomal dominant, 2 (ADTKD2) [MIM:174000]: A form of autosomal dominant tubulointerstitial kidney disease, a genetically heterogeneous disorder characterized by slowly progressive loss of kidney function, bland urinary sediment, hyperuricemia, absent or mildly increased albuminuria, lack of severe hypertension during the early stages, and normal or small kidneys on ultrasound. Renal histology shows variable abnormalities including interstitial fibrosis with tubular atrophy, microcystic dilatation of the tubules, thickening of tubular basement membranes, medullary cysts, and secondary glomerulosclerotic or glomerulocystic changes with abnormal glomerular tufting. There is significant variability, as well as incomplete penetrance. {ECO:0000269|PubMed:23396133}. The disease is caused by variants affecting the gene represented in this entry.

NA

NA

EC 1.14.11.-

3D-structure; Alternative splicing; Chromatin regulator; Dioxygenase; Iron; Metal-binding; Neurogenesis; Nucleus; Oxidoreductase; Phosphoprotein; Proteomics identification; Reference proteome; Transcription; Transcription regulation; Zinc; Zinc-finger

A

42365.5

366

0.12

41.95

6.3

-3.09

-5.53

UCHL3

Homo sapiens (Human)

Ubiquitin carboxyl-terminal hydrolase isozyme L3; UCH-L3

Peptidase C12 family

Peptidase

Thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of either ubiquitin or NEDD8. Has a 10-fold preference for Arg and Lys at position P3", and exhibits a preference towards 'Lys-48'-linked ubiquitin chains. Deubiquitinates ENAC in apical compartments, thereby regulating apical membrane recycling. Indirectly increases the phosphorylation of IGFIR, AKT and FOXO1 and promotes insulin-signaling and insulin-induced adipogenesis. Required for stress-response retinal, skeletal muscle and germ cell maintenance. May be involved in working memory. Can hydrolyze UBB(+1), a mutated form of ubiquitin which is not effectively degraded by the proteasome and is associated with neurogenerative disorders. Deubiquitinating enzyme (DUB) that controls levels of cellular ubiquitin through processing of ubiquitin precursors and ubiquitinated proteins.

Epilepsy, familial focal, with variable foci 4 (FFEVF4) [MIM:617935]: An autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions, including the temporal, frontal, parietal, and occipital lobes. Seizure types commonly include temporal lobe epilepsy, frontal lobe epilepsy, and nocturnal frontal lobe epilepsy. Some patients may have intellectual disability or autism spectrum disorders. Seizure onset usually occurs in the first or second decades, although later onset has been reported, and there is phenotypic variability within families. A subset of patients have structural brain abnormalities. Penetrance of the disorder is incomplete. FFEVF4 is characterized by onset of focal seizures in the first years of life. {ECO:0000269|PubMed:24157691, ECO:0000269|PubMed:28235671}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Developmental and epileptic encephalopathy 62 (DEE62) [MIM:617938]: 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. DEE62 is characterized by onset of seizures in the first year of life. {ECO:0000269|PubMed:29466837}. The disease is caused by variants affecting the gene represented in this entry.

NA

Q9H078; G5E9A7; Q15797; Q7Z699

EC 3.4.19.12

3D-structure; Cytoplasm; Hydrolase; Phosphoprotein; Protease; Proteomics identification; Reference proteome; Thiol protease; Ubl conjugation pathway

A,B

34540.8

304

0.07

39.91

5.01

-17.24

-5.52

MAT2A

Homo sapiens (Human)

Methionine adenosyltransferase II; Methionine adenosyltransferase 2; MAT-II; MAT 2; AdoMet synthase 2

AdoMet synthase family

AdoMet synthase family

Catalyzes the formation of S-adenosylmethionine from methionine and ATP. The reaction comprises two steps that are both catalyzed by the same enzyme: formation of S-adenosylmethionine (AdoMet) and triphosphate, and subsequent hydrolysis of the triphosphate.

Pyruvate kinase hyperactivity (PKHYP) [MIM:102900]: Autosomal dominant phenotype characterized by increase of red blood cell ATP. {ECO:0000269|PubMed:9090535}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Pyruvate kinase deficiency of red cells (PKRD) [MIM:266200]: A frequent cause of hereditary non-spherocytic hemolytic anemia. Clinically, pyruvate kinase-deficient patients suffer from a highly variable degree of chronic hemolysis, ranging from severe neonatal jaundice and fatal anemia at birth, severe transfusion-dependent chronic hemolysis, moderate hemolysis with exacerbation during infection, to a fully compensated hemolysis without apparent anemia. {ECO:0000269|PubMed:10087985, ECO:0000269|PubMed:10772876, ECO:0000269|PubMed:11328279, ECO:0000269|PubMed:11960989, ECO:0000269|PubMed:1536957, ECO:0000269|PubMed:1896471, ECO:0000269|PubMed:19085939, ECO:0000269|PubMed:2018831, ECO:0000269|PubMed:21794208, ECO:0000269|PubMed:7706479, ECO:0000269|PubMed:8161798, ECO:0000269|PubMed:8180378, ECO:0000269|PubMed:8476433, ECO:0000269|PubMed:8481523, ECO:0000269|PubMed:8483951, ECO:0000269|PubMed:8664896, ECO:0000269|PubMed:8807089, ECO:0000269|PubMed:9075576, ECO:0000269|PubMed:9482576, ECO:0000269|PubMed:9827908, ECO:0000269|PubMed:9886305, ECO:0000269|Ref.24}. The disease is caused by variants affecting the gene represented in this entry.

DB00118; DB00134

Q96IK1-2; Q96NX5; Q6ZP82-1; Q8IUI8; Q6P1L5; P15976-2; P80217-2; Q8WZ19; Q9UIH9; Q00266; P31153; Q9NZL9; P02795; Q9BRX2; O43663; O43741; P57052; Q8N488; P08195-4; Q13573; Q86W54-2; O95789-4

EC 2.5.1.6

3D-structure; Acetylation; Alternative splicing; ATP-binding; Isopeptide bond; Magnesium; Metal-binding; Nucleotide-binding; One-carbon metabolism; Phosphoprotein; Potassium; Proteomics identification; Reference proteome; Transferase; Ubl conjugation

A

42071.4

381

0.08

38.24

6.21

-4.13

-5.52

MAT1A

Homo sapiens (Human)

NA

MATA1;AMS1

AdoMet synthase family

Transferase

ATP binding.Identical protein binding.Metal ion binding.Methionine adenosyltransferase activity.Selenomethionine adenosyltransferase activity.

Methionine adenosyltransferase deficiency (MATD) [MIM:250850]: An inborn error of metabolism resulting in isolated hypermethioninemia. Most patients have no clinical abnormalities, although some neurologic symptoms may be present in rare cases with severe loss of methionine adenosyltransferase activity. {ECO:0000269|PubMed:10677294, ECO:0000269|PubMed:7560086, ECO:0000269|PubMed:8770875, ECO:0000269|PubMed:9042912}. The disease is caused by variants affecting the gene represented in this entry.

DB03191; DB00118; DB03611; DB00134

P05067; P42858; Q00266; P31153

2.5.1.6

3D-structure; ATP-binding; Disease variant; Disulfide bond; Magnesium; Metal-binding; Nucleotide-binding; One-carbon metabolism; Potassium; Proteomics identification; Reference proteome; S-nitrosylation; Transferase

A

42222.9

381

0.08

41.95

6.14

-4.58

-5.52

USP1

Homo sapiens (Human)

hUBP; Ubiquitin-specific-processing protease 1; Ubiquitin thioesterase 1; Ubiquitin carboxyl-terminal hydrolase 1

Peptidase C19 family

Peptidase

Involved in PCNA-mediated translesion synthesis (TLS) by deubiquitinating monoubiquitinated PCNA. Has almost no deubiquitinating activity by itself and requires the interaction with WDR48 to have a high activity. Negative regulator of DNA damage repair which specifically deubiquitinates monoubiquitinated FANCD2.

Brachydactyly A2 (BDA2) [MIM:112600]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. In brachydactyly type A2 shortening of the middle phalanges is confined to the index finger and the second toe, all other digits being more or less normal. Because of a rhomboid or triangular shape of the affected middle phalanx, the end of the second finger usually deviates radially. {ECO:0000269|PubMed:19327734, ECO:0000269|PubMed:21357617}. The gene represented in this entry is involved in disease pathogenesis. Duplications of a cis-regulatory element located approximately 110 kb downstream of BMP2 have been found in BDA2 families. They likely cause altered BMP2 expression with pathological consequences. {ECO:0000269|PubMed:19327734, ECO:0000269|PubMed:21357617}.; DISEASE: Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1 (SSFSC1) [MIM:617877]: An autosomal dominant disorder characterized by short stature, facial dysmorphism, skeletal anomalies, and variable cardiac defects. Distinctive facial features include midface retrusion, short upturned nose, long philtrum, high-arched or cleft palate, and variable degrees of micrognathia and dental crowding. Skeletal anomalies include patterning defects of the axial skeleton, characterized by 11 pairs of ribs and brachydactyly of the fifth ray. Congenital heart defects are variably observed and appear to involve primarily the cardiac outflow tract. {ECO:0000269|PubMed:29198724}. The disease is caused by variants affecting the gene represented in this entry.

NA

Q8TAF3; Q8TAF3-1

EC 3.4.19.12

3D-structure; Autocatalytic cleavage; DNA damage; DNA repair; Hydrolase; Nucleus; Phosphoprotein; Protease; Proteomics identification; Reference proteome; Thiol protease; Ubl conjugation; Ubl conjugation pathway

D

32426

285

0.1

50.73

5.85

-4.67

-5.51

ARSA

Homo sapiens (Human)

Cerebrosidesulfatase; Arylsulfatase A component C; ASA; ARSA

Sulfatase family

Sulfuric ester hydrolase

Hydrolyzes cerebroside sulfate.

Metachromatic leukodystrophy (MLD) [MIM:250100]: An autosomal recessive disease caused by abnormal intralysosomal accumulation of cerebroside-3-sulfate in central and peripheral nervous systems, as well as other organs. MLD is clinically characterized by leukodystrophy, progressive demyelination and a variety of neurological symptoms, including gait disturbances, ataxias, optical atrophy, dementia, seizures, and spastic tetraparesis. Decreased arylsulfatase A activity is detected in urine, leukocytes, and fibroblasts of affected individuals. Several forms of the disease can be distinguished according to the age at onset and disease severity: late infantile, juvenile and adult forms, partial cerebroside sulfate deficiency, and pseudoarylsulfatase A deficiency. Individuals with pseudoarylsulfatase A deficiency have low arylsulfatase A activity but lack neurological manifestations and are apparently healthy. {ECO:0000269|PubMed:10220151, ECO:0000269|PubMed:10381328, ECO:0000269|PubMed:10477432, ECO:0000269|PubMed:10533072, ECO:0000269|PubMed:10751093, ECO:0000269|PubMed:11020646, ECO:0000269|PubMed:11061266, ECO:0000269|PubMed:11456299, ECO:0000269|PubMed:11941485, ECO:0000269|PubMed:12503099, ECO:0000269|PubMed:12788103, ECO:0000269|PubMed:1353340, ECO:0000269|PubMed:14517960, ECO:0000269|PubMed:14680985, ECO:0000269|PubMed:15026521, ECO:0000269|PubMed:15326627, ECO:0000269|PubMed:15710861, ECO:0000269|PubMed:1670590, ECO:0000269|PubMed:1673291, ECO:0000269|PubMed:1678251, ECO:0000269|PubMed:18693274, ECO:0000269|PubMed:19606494, ECO:0000269|PubMed:20339381, ECO:0000269|PubMed:21265945, ECO:0000269|PubMed:2574462, ECO:0000269|PubMed:7581401, ECO:0000269|PubMed:7825603, ECO:0000269|PubMed:7860068, ECO:0000269|PubMed:7902317, ECO:0000269|PubMed:7906588, ECO:0000269|PubMed:7909527, ECO:0000269|PubMed:8095918, ECO:0000269|PubMed:8101038, ECO:0000269|PubMed:8101083, ECO:0000269|PubMed:8104633, ECO:0000269|PubMed:8891236, ECO:0000269|PubMed:9090526, ECO:0000269|PubMed:9272717, ECO:0000269|PubMed:9452102, ECO:0000269|PubMed:9490297, ECO:0000269|PubMed:9600244, ECO:0000269|PubMed:9819708}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Multiple sulfatase deficiency (MSD) [MIM:272200]: A clinically and biochemically heterogeneous disorder caused by the simultaneous impairment of all sulfatases, due to defective post-translational modification and activation. It combines features of individual sulfatase deficiencies such as metachromatic leukodystrophy, mucopolysaccharidosis, chondrodysplasia punctata, hydrocephalus, ichthyosis, neurologic deterioration and developmental delay. {ECO:0000269|PubMed:15146462}. The protein represented in this entry is involved in disease pathogenesis. Arylsulfatase A activity is impaired in multiple sulfatase deficiency due to mutations in SUMF1 (PubMed:15146462). SUMF1 mutations result in defective post-translational modification of ARSA at residue Cys-69 that is not converted to 3-oxoalanine (PubMed:7628016). {ECO:0000269|PubMed:15146462, ECO:0000269|PubMed:7628016}.

DB03821; DB01800; DB01141; DB04786

P50995; Q6P5X5; Q13554-3; O60826; Q96D98; Q9H0I2; Q12951-2; Q16512; P28069; O75360; Q9BQY4; Q15645; O95231

EC 3.1.6.8

3D-structure; Alternative splicing; Calcium; Direct protein sequencing; Disease variant; Disulfide bond; Endoplasmic reticulum; Glycoprotein; Hydrolase; Ichthyosis; Leukodystrophy; Lipid metabolism; Lysosome; Metachromatic leukodystrophy; Metal-binding; Proteomics identification; Reference proteome; Signal

P

51173.7

481

0.09

47.42

5.59

-12.84

-5.51

poxB

Escherichia coli (strain K12)

NA

b0871;JW0855

TPP enzyme family

Oxidoreductase

Flavin adenine dinucleotide binding.Identical protein binding.Lipid binding.Magnesium ion binding.Pyruvate dehydrogenase (quinone) activity.Thiamine pyrophosphate binding.

Glycogen storage disease 6 (GSD6) [MIM:232700]: A metabolic disorder characterized by mild to moderate hypoglycemia, mild ketosis, growth retardation, and prominent hepatomegaly. Heart and skeletal muscle are not affected. {ECO:0000269|PubMed:9529348}. The disease is caused by variants affecting the gene represented in this entry.

NA

P07003

1.2.5.1

3D-structure; Cell inner membrane; Cell membrane; Direct protein sequencing; FAD; Flavoprotein; Lipid-binding; Magnesium; Membrane; Metal-binding; Nucleotide-binding; Oxidoreductase; Pyruvate; Reference proteome; Thiamine pyrophosphate; Ubiquinone

A,B,C,D,E,F,G,H,I,J,K,L

113027

1046

0.07

35.99

5.75

-24.38

-5.49

fabB

Escherichia coli (strain K12)

NA

JW2320;fabC;b2323

Thiolase-like superfamily, Beta-ketoacyl-ACP synthases family

Transferase

3-oxoacyl-[acyl-carrier-protein] synthase 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.

DB08627; DB08628; DB08359; DB04302; DB03600; DB04519; DB01034; DB03017

NA

2.3.1.41

3D-structure; Acyltransferase; Cytoplasm; Direct protein sequencing; Fatty acid biosynthesis; Fatty acid metabolism; Lipid biosynthesis; Lipid metabolism; Reference proteome; Transferase

A,B,C,D

40198.1

383

0.06

38.17

5.17

-13.62

-5.5

bglA

Paenibacillus polymyxa (Bacillus polymyxa)

NA

NA

Glycosyl hydrolase 1 family

Hydrolase

Beta-glucosidase activity.Scopolin beta-glucosidase activity.

Schizophrenia (SCZD) [MIM:181500]: A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. {ECO:0000269|PubMed:15645182}. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

DB02658; DB04282; DB04304

NA

3.2.1.21

3D-structure; Carbohydrate metabolism; Cellulose degradation; Glycosidase; Hydrolase; Polysaccharide degradation

A

51515.2

447

0.14

38.44

5.28

-18.1

-5.49

xlnA

Streptomyces lividans

NA

NA

Glycosyl hydrolase 10 (cellulase F) family

Hydrolase

Carbohydrate binding.Endo-1,4-beta-xylanase activity.

Isovaleric acidemia (IVA) [MIM:243500]: A metabolic disorder characterized by retarded psychomotor development, a peculiar odor resembling sweaty feet, an aversion to dietary protein, and pernicious vomiting, leading to acidosis and coma. The acute neonatal form leads to massive metabolic acidosis from the first days of life and rapid death. {ECO:0000269|PubMed:2063866, ECO:0000269|PubMed:22004070, ECO:0000269|PubMed:22350545, ECO:0000269|PubMed:23587913, ECO:0000269|PubMed:28535199, ECO:0000269|PubMed:9665741}. The disease is caused by variants affecting the gene represented in this entry.

DB03389; DB03366; DB04465

NA

3.2.1.8

3D-structure; Carbohydrate metabolism; Direct protein sequencing; Disulfide bond; Glycosidase; Hydrolase; Lectin; Polysaccharide degradation; Secreted; Signal; Xylan degradation

A

33113.2

302

0.1

31.62

6.24

-1.74

-5.5

cocE

Rhodococcus sp. (strain MB1 Bresler)

NA

NA

CocE/NonD hydrolase family

Hydrolase

Carboxylic ester hydrolase activity.Dipeptidyl-peptidase activity.

Thiamine metabolism dysfunction syndrome 5, episodic encephalopathy type (THMD5) [MIM:614458]: An autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits. {ECO:0000269|PubMed:22152682}. The disease is caused by variants affecting the gene represented in this entry.

DB03793; DB01795

NA

3.1.1.84

3D-structure; Cytoplasm; Direct protein sequencing; Hydrolase; Serine esterase

A

62127.9

574

0.09

26.62

4.56

-33.24

-5.5

PHF8

Homo sapiens (Human)

ZNF422; PHD finger protein 8; KIAA1111

JHDM1 histone demethylase family, JHDM1D subfamily

Paired donor oxygen oxidoreductase

Demethylates mono- and dimethylated histone H3 'Lys-9' residue (H3K9Me1 and H3K9Me2), dimethylated H3 'Lys-27' (H3K27Me2) and monomethylated histone H4 'Lys-20' residue (H4K20Me1). Acts as a transcription activator as H3K9Me1, H3K9Me2, H3K27Me2 and H4K20Me1 are epigenetic repressive marks. Involved in cell cycle progression by being required to control G1-S transition. Acts as a coactivator of rDNA transcription, by activating polymerase I (pol I) mediated transcription of rRNA genes. Required for brain development, probably by regulating expression of neuron-specific genes. Only has activity toward H4K20Me1 when nucleosome is used as a substrate and when not histone octamer is used as substrate. May also have weak activity toward dimethylated H3 'Lys-36' (H3K36Me2), however, the relevance of this result remains unsure in vivo. Specifically binds trimethylated 'Lys-4' of histone H3 (H3K4me3), affecting histone demethylase specificity: has weak activity toward H3K9Me2 in absence of H3K4me3, while it has high activity toward H3K9me2 when binding H3K4me3. Histone lysine demethylase with selectivity for the di- and monomethyl states that plays a key role cell cycle progression, rDNA transcription and brain development.

Intellectual developmental disorder, X-linked, syndromic, Siderius type (MRXSSD) [MIM:300263]: A syndrome characterized by mild to borderline intellectual disability with or without cleft lip/cleft palate. {ECO:0000269|PubMed:16199551, ECO:0000269|PubMed:17661819, ECO:0000269|PubMed:20101266, ECO:0000269|PubMed:20208542, ECO:0000269|PubMed:20346720, ECO:0000269|PubMed:20421419, ECO:0000269|PubMed:20548336, ECO:0000269|PubMed:20622853, ECO:0000269|PubMed:20622854, ECO:0000269|PubMed:31691806}. The disease is caused by variants affecting the gene represented in this entry.

NA

Q96QS3; Q06330; Q9Y462; P51610-1; Q15156; P10276

EC 1.14.11.27

3D-structure; Activator; Alternative splicing; Cell cycle; Chromatin regulator; Dioxygenase; Disease variant; Intellectual disability; Iron; Metal-binding; Nucleus; Oxidoreductase; Phosphoprotein; Proteomics identification; Reference proteome; Transcription; Transcription regulation; Zinc; Zinc-finger

A,B

51141.1

446

0.11

44.47

6.21

-4.56

-5.5

Malaria DXR

Plasmodium falciparum (isolate HB3)

IspC; DXR; DXP reductoisomerase; DOXP reductoisomerase; 2-C-Methyl-d-erythritol 4-phosphate synthase; 1-deoxyxylulose-5-phosphate reductoisomerase

DXR family

Short-chain dehydrogenases reductase

Catalyzes the NADP-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP).

Ichthyosis, congenital, autosomal recessive 11 (ARCI11) [MIM:602400]: A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. {ECO:0000269|PubMed:17273967, ECO:0000269|PubMed:18843291}. The disease is caused by variants affecting the gene represented in this entry.

NA

NA

EC 1.1.1.267

3D-structure; Apicoplast; Isoprene biosynthesis; Magnesium; Manganese; Metal-binding; NADP; Oxidoreductase; Plastid; Transit peptide

A

46644.4

410

0.09

36.77

6.95

-0.14

-5.5

HRH3

Homo sapiens (Human)

Histamine receptor 3; HH3R; GPCR97; G-protein coupled receptor 97; G protein-coupled receptor 97

G-protein coupled receptor 1 family

GPCR rhodopsin

Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist). Agonist stimulation of isoform 3 neither modified adenylate cyclase activity nor induced intracellular calcium mobilization. The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system.

Immunodeficiency 48 (IMD48) [MIM:269840]: A form of severe immunodeficiency characterized by a selective absence of CD8+ T-cells. {ECO:0000269|PubMed:11123350, ECO:0000269|PubMed:11412303, ECO:0000269|PubMed:18509675, ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8202713}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Autoimmune disease, multisystem, infantile-onset, 2 (ADMIO2) [MIM:617006]: An autosomal recessive, autoimmune disorder characterized by systemic manifestations including blistering skin disease, uncontrollable bullous pemphigoid, inflammatory colitis, autoimmune hypothyroidism, proteinuria and nephrotic syndrome. {ECO:0000269|PubMed:26783323}. The disease is caused by variants affecting the gene represented in this entry.

DB01238; DB06698; DB05381; DB17087; DB05080; DB00768; DB11642

NA

NA

3D-structure; Alternative splicing; Cell membrane; Disulfide bond; G-protein coupled receptor; Glycoprotein; Membrane; Phosphoprotein; Proteomics identification; Receptor; Reference proteome; Transducer; Transmembrane; Transmembrane helix

A

34321.1

301

0.16

32.22

9.63

15.11

-5.49