SDS

Homo sapiens (Human)

NA

SDH

Serine/threonine dehydratase family

Lyase

L-serine ammonia-lyase activity.L-threonine ammonia-lyase activity.Protein homodimerization activity.Pyridoxal phosphate binding.

Immunodeficiency, common variable, 12, with autoimmunity (CVID12) [MIM:616576]: A primary immunodeficiency characterized by hypogammaglobulinemia and recurrent bacterial infections. About half of patients develop autoimmune features, including cytopenia, as well as generalized inflammation and lymphoproliferation manifest as lymphadenopathy or hepatosplenomegaly. {ECO:0000269|PubMed:26279205}. The disease is caused by variants affecting the gene represented in this entry.

DB00114; DB00133

Q8WTU0; O14964; Q96PF1

4.3.1.17; 4.3.1.19

3D-structure; Cytoplasm; Direct protein sequencing; Gluconeogenesis; Lipid metabolism; Lyase; Proteomics identification; Pyridoxal phosphate; Reference proteome

A

33559.7

319

0.06

34.65

7.2

0.42

-8.14

HNMT

Homo sapiens (Human)

Histamine-N-methyltransferase; HNMT; HMT

Class I-like SAM-binding methyltransferase superfamily, HNMT family

Methyltransferase

Inactivates histamine by N-methylation. Plays an important role in degrading histamine and in regulating the airway response to histamine.

Intellectual developmental disorder, autosomal recessive 51 (MRT51) [MIM:616739]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:26206890}. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry.

DB00613; DB13875; DB05381; DB04655; DB01103; DB01752; DB07106

NA

EC 2.1.1.8

3D-structure; Alternative splicing; Cytoplasm; Disease variant; Intellectual disability; Methyltransferase; Proteomics identification; Reference proteome; S-adenosyl-L-methionine; Transferase

A,B

32712

288

0.1

36.38

5.18

-9.97

-8.14

por

Desulfocurvibacter africanus (Desulfovibrio africanus)

NA

NA

Pyruvate:ferredoxin/flavodoxin oxidoreductase family

Oxidoreductase

4 iron, 4 sulfur cluster binding.Iron ion binding.Pyruvate synthase activity.Thiamine pyrophosphate binding.

Intellectual developmental disorder, autosomal dominant 62 (MRD62) [MIM:618793]: An autosomal dominant form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD62 is characterized by mild to moderately impaired intellectual development. {ECO:0000269|PubMed:27479843, ECO:0000269|PubMed:29460436}. The disease is caused by variants affecting the gene represented in this entry.

DB02410; DB01987; DB00507

NA

1.2.7.1

3D-structure; 4Fe-4S; Calcium; Cytoplasm; Direct protein sequencing; Disulfide bond; Electron transport; Iron; Iron-sulfur; Magnesium; Metal-binding; Oxidoreductase; Pyruvate; Thiamine pyrophosphate; Transport

A,B

115569

1065

0.09

31.51

6.32

-5.62

-8.14

SGPL1

Homo sapiens (Human)

hSPL; Sphingosine-1-phosphate aldolase; SPL 1; SP-lyase 1; S1PL; KIAA1252

Group II decarboxylase family, Sphingosine-1-phosphate lyase subfamily

Carbon-carbon lyase

Elevates stress-induced ceramide production and apoptosis. Required for global lipid homeostasis in liver and cholesterol homeostasis in fibroblasts. Involved in the regulation of pro-inflammatory response and neutrophil trafficking. Modulates neuronal autophagy via phosphoethanolamine production which regulates accumulation of aggregate-prone proteins such as APP. Seems to play a role in establishing neuronal contact sites and axonal maintenance. Cleaves phosphorylated sphingoid bases (PSBs), such as sphingosine-1-phosphate, into fatty aldehydes and phosphoethanolamine.

RENI syndrome (RENI) [MIM:617575]: An autosomal recessive, steroid-resistant nephrotic syndrome that manifests in infancy or early childhood, and progresses to end-stage renal failure within a few years. Additional clinical features include ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects. In rare cases, patients present with isolated primary adrenal insufficiency. Some patients present in utero with fetal hydrops and fetal demise. {ECO:0000269|PubMed:28165339, ECO:0000269|PubMed:28165343, ECO:0000269|PubMed:28181337, ECO:0000269|PubMed:30090628}. The disease is caused by variants affecting the gene represented in this entry.

DB00114

Q92482; O43315; Q92843; Q6PL45-2; Q8NHW4; Q8N6F1-2; P52803; Q9UKR5; Q7L5A8; Q8N128-2; Q14802-3; P30519; Q01628; Q9NX47; Q6ZSS7; P30301; Q8IY49-2; Q9NXK6; Q04941; Q5VZY2; Q5GAN6; Q5QGT7; Q8TAC9; Q99726; P02808; Q86WV6; Q12846; Q9UNK0; Q96HP8; Q9NWH2; Q5BJF2; O14817; A5PKU2; Q53HI1

EC 4.1.2.27

3D-structure; Acetylation; Apoptosis; Disease variant; Endoplasmic reticulum; Lipid metabolism; Lyase; Membrane; Nitration; Phosphoprotein; Proteomics identification; Pyridoxal phosphate; Reference proteome; Signal-anchor; Sphingolipid metabolism; Transmembrane; Transmembrane helix

A,B

97521.7

887

0.1

32.99

8.97

18.32

-8.14

KMT5B

Homo sapiens (Human)

Lysine N-methyltransferase 5B; Lysine-specific methyltransferase 5B; Suppressor of variegation 4-20 homolog 1; Su(var)4-20 homolog 1; Suv4-20h1; [histone H4]-N-methyl-L-lysine20 N-methyltransferase KM

Class V-like SAM-binding methyltransferase superfamily, Histone-lysine methyltransferase family, Suvar4-20 subfamily

NA

Histone methyltransferase that specifically methylates monomethylated 'Lys-20' (H4K20me1) and dimethylated 'Lys-20' (H4K20me2) of histone H4 to produce respectively dimethylated 'Lys-20' (H4K20me2) and trimethylated 'Lys-20' (H4K20me3) and thus regulates transcription and maintenance of genome integrity. In vitro also methylates unmodified 'Lys-20' (H4K20me0) of histone H4 and nucleosomes. H4 'Lys-20' trimethylation represents a specific tag for epigenetic transcriptional repression. Mainly functions in pericentric heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin in these regions. KMT5B is targeted to histone H3 via its interaction with RB1 family proteins (RB1, RBL1 and RBL2) (By similarity). Plays a role in myogenesis by regulating the expression of target genes, such as EID3. Facilitates TP53BP1 foci formation upon DNA damage and proficient non-homologous end-joining (NHEJ)-directed DNA repair by catalyzing the di- and trimethylation of 'Lys-20' of histone H4. May play a role in class switch reconbination by catalyzing the di- and trimethylation of 'Lys-20' of histone H4 (By similarity).

Intellectual developmental disorder, autosomal dominant 51 (MRD51) [MIM:617788]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:28191889, ECO:0000269|PubMed:29276005}. The disease is caused by variants affecting the gene represented in this entry.

NA

Q9H2G4; Q61026

EC 2.1.1.361

3D-structure; Alternative splicing; Chromatin regulator; Chromosome; Disease variant; Intellectual disability; Isopeptide bond; Metal-binding; Methyltransferase; Myogenesis; Nucleus; Proteomics identification; Reference proteome; Repressor; S-adenosyl-L-methionine; Transcription; Transcription regulation; Transferase; Ubl conjugation; Zinc

A

26230.2

233

0.11

42.29

5.64

-6.07

-8.14

CDK8

Homo sapiens (Human)

Protein kinase K35; Mediator of RNA polymerase II transcription subunit CDK8; Mediator complex subunit CDK8; Cell division protein kinase 8

Protein kinase superfamily, CMGC Ser/Thr protein kinase family, CDC2/CDKX subfamily

Kinase

Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation. Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes.

Intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA) [MIM:618748]: An autosomal dominant neurodevelopmental disorder with onset in infancy. IDDHBA is characterized by hypotonia, global developmental delay, learning disability, and behavioral abnormalities, such as autistic features and attention deficit-hyperactivity disorder. Additional variable features may include non-specific facial dysmorphism, congenital heart defects, ocular anomalies, and poor feeding. {ECO:0000269|PubMed:30905399}. The disease is caused by variants affecting the gene represented in this entry.

DB03496

P24863; Q01094; P02489; Q14204; Q92876

EC 2.7.11.22

3D-structure; Activator; Alternative splicing; ATP-binding; Autism spectrum disorder; Disease variant; Intellectual disability; Kinase; Nucleotide-binding; Nucleus; Proteomics identification; Reference proteome; Repressor; Serine/threonine-protein kinase; Transcription; Transcription regulation; Transferase

A

37655.2

321

0.11

37.04

8.56

5.13

-8.14

PRKAR1A

Homo sapiens (Human)

cAMP-dependent protein kinase type I-alpha regulatory subunit; Tissue-specific extinguisher 1; TSE1; PRKAR1; PKR1

CAMP-dependent kinase regulatory chain family

Kinase

Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells.

Carney complex 1 (CNC1) [MIM:160980]: CNC is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, and psammomatous melanotic schwannomas. {ECO:0000269|PubMed:15371594, ECO:0000269|PubMed:18241045, ECO:0000269|PubMed:22785148, ECO:0000269|PubMed:23323113, ECO:0000269|PubMed:26405036}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Intracardiac myxoma (INTMYX) [MIM:255960]: Inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Primary pigmented nodular adrenocortical disease 1 (PPNAD1) [MIM:610489]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. PPNAD1 is most often diagnosed in patients with Carney complex, a multiple neoplasia syndrome. However it can also be observed in patients without other manifestations. {ECO:0000269|PubMed:12213893}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Acrodysostosis 1, with or without hormone resistance (ACRDYS1) [MIM:101800]: A form of skeletal dysplasia characterized by short stature, severe brachydactyly, facial dysostosis, and nasal hypoplasia. Affected individuals often have advanced bone age and obesity. Laboratory studies show resistance to multiple hormones, including parathyroid, thyrotropin, calcitonin, growth hormone-releasing hormone, and gonadotropin. However, not all patients show endocrine abnormalities. {ECO:0000269|PubMed:21651393, ECO:0000269|PubMed:22464250, ECO:0000269|PubMed:22464252, ECO:0000269|PubMed:22723333, ECO:0000269|PubMed:23043190, ECO:0000269|PubMed:23425300, ECO:0000269|PubMed:26405036}. The disease is caused by variants affecting the gene represented in this entry.

DB01790; DB02527; DB02315; DB05798

Q9GZX7; P24588; O43687-2; Q9BSF0; Q9H6J7-2; Q86Y01; P0C7A2-2; Q9H0R8; Q9H8W4; P17612; P31321; P51817; P35250; Q86UC2; Q01105; Q8N0X7; O96006; P03259-2

NA

3D-structure; Acetylation; Alternative splicing; cAMP; cAMP-binding; Cell membrane; Cushing syndrome; Direct protein sequencing; Disease variant; Disulfide bond; Membrane; Nucleotide-binding; Phosphoprotein; Proteomics identification; Reference proteome; Repeat

A

17007.4

149

0.08

49.36

6.36

-0.52

-8.14

Bact botA

Clostridium botulinum

botA

Peptidase M27 family

Peptidase

Inhibits acetylcholine release. The botulinum toxin binds with high affinity to peripheral neuronal presynaptic membrane to the secretory vesicle protein SV2. It binds directly to the largest luminal loop of SV2A, SV2B and SV2C. It is then internalized by receptor-mediated endocytosis. The C-terminus of the heavy chain (H) is responsible for the adherence of the toxin to the cell surface while the N-terminus mediates transport of the light chain from the endocytic vesicle to the cytosol. After translocation, the light chain (L) hydrolyzes the 197-Gln-|-Arg- 198 bond in SNAP-25, thereby blocking neurotransmitter release. Inhibition of acetylcholine release results in flaccid paralysis, with frequent heart or respiratory failure.

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

Q02563; Q496J9; Q9Z2I6

NA

3D-structure; Cell wall; Direct protein sequencing; Disulfide bond; Host cell membrane; Host cytoplasm; Host cytoplasmic vesicle; Host membrane; Host synapse; Hydrolase; Lipid-binding; Membrane; Metal-binding; Metalloprotease; Neurotoxin; Pharmaceutical; Protease; Secreted; Toxin; Transmembrane; Transmembrane helix; Ubl conjugation; Virulence; Zinc

A

47759.6

417

0.13

21.7

6.36

-1.96

-8.14

DLD

Homo sapiens (Human)

NA

PHE3;LAD;GCSL

Class-I pyridine nucleotide-disulfide oxidoreductase family

Oxidoreductase

Dihydrolipoyl dehydrogenase activity.Electron carrier activity.Flavin adenine dinucleotide binding.Lipoamide binding.NAD binding.

Dihydrolipoamide dehydrogenase deficiency (DLDD) [MIM:246900]: An autosomal recessive metabolic disorder characterized biochemically by a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). Clinically, affected individuals have lactic acidosis and neurologic deterioration due to sensitivity of the central nervous system to defects in oxidative metabolism. {ECO:0000269|PubMed:10448086, ECO:0000269|PubMed:11687750, ECO:0000269|PubMed:12925875, ECO:0000269|PubMed:15712224, ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:16770810, ECO:0000269|PubMed:17404228, ECO:0000269|PubMed:20160912, ECO:0000269|PubMed:8506365, ECO:0000269|PubMed:8968745, ECO:0000269|PubMed:9540846, ECO:0000269|PubMed:9934985}. The disease is caused by variants affecting the gene represented in this entry.

DB03147; DB00145; DB00157

P42858; O14713; O00330; P30041; P62258

1.8.1.4

3D-structure; Acetylation; Alternative splicing; Cell projection; Cilium; Cytoplasmic vesicle; Disease variant; Disulfide bond; FAD; Flagellum; Flavoprotein; Mitochondrion; NAD; Nucleus; Oxidoreductase; Phosphoprotein; Proteomics identification; Redox-active center; Reference proteome; Transit peptide

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

49832.7

471

0.06

26.19

6.51

-2.02

-8.13

pchF

Pseudomonas putida (Arthrobacter siderocapsulatus)

NA

NA

NA

Oxidoreductase

4-cresol dehydrogenase (hydroxylating) activity.Flavin adenine dinucleotide binding.Oxidoreductase activity, acting on CH-OH group of donors.

Dihydrolipoamide dehydrogenase deficiency (DLDD) [MIM:246900]: An autosomal recessive metabolic disorder characterized biochemically by a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). Clinically, affected individuals have lactic acidosis and neurologic deterioration due to sensitivity of the central nervous system to defects in oxidative metabolism. {ECO:0000269|PubMed:10448086, ECO:0000269|PubMed:11687750, ECO:0000269|PubMed:12925875, ECO:0000269|PubMed:15712224, ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:16770810, ECO:0000269|PubMed:17404228, ECO:0000269|PubMed:20160912, ECO:0000269|PubMed:8506365, ECO:0000269|PubMed:8968745, ECO:0000269|PubMed:9540846, ECO:0000269|PubMed:9934985}. The disease is caused by variants affecting the gene represented in this entry.

DB03147

NA

1.17.9.1

3D-structure; Direct protein sequencing; FAD; Flavoprotein; Oxidoreductase; Plasmid

A

57240.8

515

0.1

30.94

6.06

-4.42

-8.13

NOS2

Homo sapiens (Human)

iNOS; Peptidyl-cysteine S-nitrosylase NOS2; Nitric oxide synthase, inducible; NOS2A; NOS type II; Inducible NOS; Inducible NO synthase; Hepatocyte NOS; HEP-NOS

NOS family

Paired donor oxygen oxidoreductase

Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such PTGS2/COX2 (By similarity). As component of the iNOS-S100A8/9 transnitrosylase complex involved in the selective inflammatory stimulus-dependent S-nitrosylation of GAPDH on 'Cys-247' implicated in regulation of the GAIT complex activity and probably multiple targets including ANXA5, EZR, MSN and VIM. Involved in inflammation, enhances the synthesis of proinflammatory mediators such as IL6 and IL8.

Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome 3 (CAMRQ3) [MIM:613227]: An autosomal recessive, congenital cerebellar ataxia associated with dysarthia, quadrupedal gait and intellectual disability. {ECO:0000269|PubMed:19461874}. The disease is caused by variants affecting the gene represented in this entry.

DB07003; DB07007; DB07011; DB07405; DB08750; DB01997; DB07029; DB07008; DB08214; DB07002; DB01835; DB06879; DB04534; DB03100; DB02207; DB00125; DB00155; DB01234; DB14649; DB11327; DB00997; DB07306; DB07388; DB05252; DB01381; DB03366; DB05214; DB04400; DB09237; DB00244; DB01110; DB01017; DB03144; DB01686; DB03449; DB06916; DB07318; DB07389; DB02044; DB02644; DB05383; DB02234; DB03953; DB02462; DB08814

P04406

EC 1.14.13.39

3D-structure; Alternative splicing; Calcium; Calmodulin-binding; Cytoplasm; FAD; Flavoprotein; FMN; Heme; Iron; Metal-binding; NADP; Oxidoreductase; Phosphoprotein; Proteomics identification; Reference proteome; Ubl conjugation; Zinc

A,B,C,D

48633

421

0.12

46.5

6.75

-1.04

-8.13

PDE4D

Homo sapiens (Human)

cAMP-specific 3',5'-cyclic phosphodiesterase 4D; PDE43; DPDE3

Cyclic nucleotide phosphodiesterase family, PDE4 subfamily

Phosphoric diester hydrolase

Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. {ECO:0000269|PubMed:17006457}.; DISEASE: Acrodysostosis 2, with or without hormone resistance (ACRDYS2) [MIM:614613]: A pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems. {ECO:0000269|PubMed:22464250, ECO:0000269|PubMed:22464252, ECO:0000269|PubMed:23033274, ECO:0000269|PubMed:23043190}. The disease is caused by variants affecting the gene represented in this entry.

DB06842; DB04149; DB03606; DB03183; DB04469; DB02676; DB01959; DB07051; DB04271; DB07954; DB08299; DB00131; DB01427; DB00201; DB03849; DB05219; DB00651; DB06246; DB05266; DB01088; DB01113; DB01791; DB01656; DB01954; DB05298; DB09283; DB02918

P32121; P38432; Q0D2H9; Q08AF8; P43360; Q07343; Q13077; P32121; P26769; P38432; Q96CV9; Q8IUH5

EC 3.1.4.53

3D-structure; Alternative splicing; cAMP; Cell membrane; Cytoplasm; Cytoskeleton; Disease variant; Hydrolase; Isopeptide bond; Manganese; Membrane; Metal-binding; Phosphoprotein; Proteomics identification; Reference proteome; Ubl conjugation; Zinc

A,B

37201.9

322

0.07

35.83

5.02

-21.16

-8.13

PDE7A

Homo sapiens (Human)

TM22; High affinity cAMPspecific 3',5'cyclic phosphodiesterase 7A; High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A

Cyclic nucleotide phosphodiesterase family, PDE7 subfamily

Phosphoric diester hydrolase

May have a role in muscle signal transduction. Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

Timothy syndrome (TS) [MIM:601005]: Disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities and autism. {ECO:0000269|PubMed:15454078, ECO:0000269|PubMed:15863612, ECO:0000269|PubMed:25260352, ECO:0000269|PubMed:26253506, ECO:0000269|PubMed:30023270, ECO:0000269|PubMed:30172029, ECO:0000269|PubMed:31430211}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Brugada syndrome 3 (BRGDA3) [MIM:611875]: A heart disease characterized by the association of Brugada syndrome with shortened QT intervals. Brugada syndrome is 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:17224476}. The gene represented in this entry may be involved in disease pathogenesis.; DISEASE: Long QT syndrome 8 (LQT8) [MIM:618447]: A form of long QT syndrome, a heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. LQT8 transmission pattern is consistent with autosomal dominant inheritance with incomplete penetrance. {ECO:0000269|PubMed:23677916, ECO:0000269|PubMed:24728418, ECO:0000269|PubMed:25633834, ECO:0000269|PubMed:30345660}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures (NEDHLSS) [MIM:620029]: An autosomal dominant disorder characterized by global developmental delay apparent from infancy, intellectual disability, poor or absent speech, behavioral abnormalities, and hypotonia with delayed walking or inability to walk. Additional features include epilepsy, mild skeletal defects, and non-specific dysmorphic features. {ECO:0000269|PubMed:30513141, ECO:0000269|PubMed:34163037}. The disease is caused by variants affecting the gene represented in this entry.

DB08602; DB07954; DB00201; DB09283

NA

EC 3.1.4.53

3D-structure; Alternative splicing; cAMP; Cytoplasm; Hydrolase; Metal-binding; Phosphoprotein; Proteomics identification; Reference proteome

A

36692.5

317

0.1

38.24

6.47

-3.52

-8.12

EGLN2

Homo sapiens (Human)

Prolyl hydroxylase domain-containing protein 1; PHD1; Hypoxia-inducible factor prolyl hydroxylase 1; HPH-3; HIF-PH1; HIF-PH; Estrogen-induced tag6; Estrogen-induced tag 6; Egl nine homolog 2; EIT6; EI

NA

Paired donor oxygen oxidoreductase

Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle. Also regulates susceptibility to normoxic oxidative neuronal death. Links oxygen sensing to cell cycle and primary cilia formation by hydroxylating the critical centrosome component CEP192 which promotes its ubiquitination and subsequent proteasomal degradation. Hydroxylates IKBKB, mediating NF-kappaB activation in hypoxic conditions. Target proteins are preferentially recognized via a LXXLAP motif. Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins.

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.

DB00126; DB11682; DB04847; DB12255

Q16665

EC 1.14.11.29

3D-structure; Alternative initiation; Dioxygenase; Iron; Metal-binding; Nucleus; Oxidoreductase; Phosphoprotein; Proteomics identification; Reference proteome; Ubl conjugation; Vitamin C

A

25146.7

226

0.09

37.65

9.21

8.52

-8.12

DYRK3

Homo sapiens (Human)

Regulatory erythroid kinase; REDK; Dual specificity tyrosine-phosphorylation-regulated kinase 3

Protein kinase superfamily, CMGC Ser/Thr protein kinase family, MNB/DYRK subfamily

Kinase

Dual-specificity tyrosine-regulated kinases (DYRKs) autophosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. Acts as a central dissolvase of membraneless organelles during the G2-to-M transition, after the nuclear-envelope breakdown: acts by mediating phosphorylation of multiple serine and threonine residues in unstructured domains of proteins, such as SRRM1 and PCM1. Does not mediate disassembly of all membraneless organelles: disassembly of P-body and nucleolus is not regulated by DYRK3. Dissolution of membraneless organelles at the onset of mitosis is also required to release mitotic regulators, such as ZNF207, from liquid-unmixed organelles where they are sequestered and keep them dissolved during mitosis. Regulates mTORC1 by mediating the dissolution of stress granules: during stressful conditions, DYRK3 partitions from the cytosol to the stress granule, together with mTORC1 components, which prevents mTORC1 signaling. When stress signals are gone, the kinase activity of DYRK3 is required for the dissolution of stress granule and mTORC1 relocation to the cytosol: acts by mediating the phosphorylation of the mTORC1 inhibitor AKT1S1, allowing full reactivation of mTORC1 signaling. Also acts as a negative regulator of EPO-dependent erythropoiesis: may place an upper limit on red cell production during stress erythropoiesis. Inhibits cell death due to cytokine withdrawal in hematopoietic progenitor cells. Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1: this in turn inhibits p53/TP53 activity and apoptosis. Dual-specificity protein kinase that promotes disassembly of several types of membraneless organelles during mitosis, such as stress granules, nuclear speckles and pericentriolar material.

Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor-initiating cells and proliferation via its function in cell proliferation regulation.

NA

Q9H8Y8

EC 2.7.12.1

3D-structure; Alternative splicing; ATP-binding; Cell cycle; Cell division; Cytoplasm; Cytoskeleton; Kinase; Magnesium; Metal-binding; Mitosis; Nucleotide-binding; Nucleus; Phosphoprotein; Proteomics identification; Reference proteome; Serine/threonine-protein kinase; Transferase; Tyrosine-protein kinase; Ubl conjugation

A

44821.5

395

0.1

49.38

9.52

21.08

-8.13

TRBC1

Homo sapiens (Human)

TCRBC1; BV05S1J2.2

NA

NA

Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens. Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation. The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity. Constant region of T cell receptor (TR) alpha chain.

Immunodeficiency 57 with autoinflammation (IMD57) [MIM:618108]: An autosomal recessive primary immunodeficiency characterized by lymphopenia and recurrent viral, bacterial, and fungal infections. Patients exhibit early-onset inflammatory bowel disease involving the upper and lower gastrointestinal tract, and develop progressive polyarthritis. {ECO:0000269|PubMed:30026316}. The disease is caused by variants affecting the gene represented in this entry. RIPK1-deficient immune cells from IMD57 patients have impaired proinflammatory signaling leading to dysregulated cytokine secretion and are prone to necroptosis. {ECO:0000269|PubMed:30026316}.; DISEASE: Autoinflammation with episodic fever and lymphadenopathy (AIEFL) [MIM:618852]: An autosomal dominant immunologic disorder characterized by early onset of recurrent episodes of unexplained fever, lymphadenopathy, hepatosplenomegaly, and increased levels of inflammatory cytokines and chemokines in patient serum. {ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281}. The disease is caused by variants affecting the gene represented in this entry.

DB02740

NA

NA

3D-structure; Adaptive immunity; Cell membrane; Disulfide bond; Glycoprotein; Immunity; Immunoglobulin domain; Membrane; Proteomics identification; Receptor; Reference proteome; T cell receptor; Transmembrane; Transmembrane helix

C,B,A

84668.2

736

0.13

39.96

5.8

-14.36

-8.13

FOLR2

Homo sapiens (Human)

Placental folate-binding protein; Folate receptor, fetal/placental; Folate receptor type-beta; Folate receptor 2; FR-beta; FOLR2

Folate receptor family

Folate receptor

Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analogs at neutral pH. Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release.

Acute hepatic porphyria (AHEPP) [MIM:612740]: A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. AHP is characterized by attacks of gastrointestinal disturbances, abdominal colic, paralyses and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors. {ECO:0000269|PubMed:10706561, ECO:0000269|PubMed:1309003, ECO:0000269|PubMed:1569184, ECO:0000269|PubMed:17236137, ECO:0000269|PubMed:2063868}. The disease is caused by variants affecting the gene represented in this entry.

DB00158; DB00563; DB05168

NA

NA

3D-structure; Cell membrane; Direct protein sequencing; Disulfide bond; Folate-binding; Glycoprotein; GPI-anchor; Lipoprotein; Membrane; Proteomics identification; Receptor; Reference proteome; Secreted; Signal; Transport

A

23841.6

205

0.12

56.78

7.92

2.58

-8.12

CYP2B6

Homo sapiens (Human)

Cytochrome P450 IIB1; CYPIIB6; 1,4-cineole 2-exo-monooxygenase

Cytochrome P450 family

Paired donor oxygen oxidoreductase

In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,4-cineole 2-exo-monooxygenase. Cytochromes P450 are a group of heme-thiolate monooxygenases.

Aromatic L-amino-acid decarboxylase deficiency (AADCD) [MIM:608643]: An inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency. It causes developmental and psychomotor delay, poor feeding, lethargy, ptosis, intermittent hypothermia, gastrointestinal disturbances. The onset is early in infancy and inheritance is autosomal recessive. {ECO:0000269|PubMed:14991824, ECO:0000269|PubMed:15079002, ECO:0000269|Ref.12}. The disease is caused by variants affecting the gene represented in this entry.

DB08369; DB02974; DB11932; DB12001; DB14973; DB15568; DB00321; DB00381; DB00701; DB01435; DB00714; DB06413; DB06697; DB13132; DB11586; DB01076; DB15011; DB00972; DB08822; DB13997; DB04975; DB01086; DB00865; DB00443; DB04794; DB12151; DB01194; DB05541; DB01222; DB01156; DB09061; DB14737; DB00564; DB06119; DB00439; DB00568; DB00604; DB00515; DB12499; DB00349; DB06470; DB00758; DB01559; DB00257; DB01394; DB05219; DB08865; DB11672; DB14635; DB04664; DB00531; DB08912; DB01151; DB16650; DB01234; DB14649; DB04856; DB00514; DB00829; DB00586; DB01184; DB00997; DB00470; DB00476; DB00625; DB15444; DB13874; DB11718; DB08899; DB00751; DB11823; DB00655; DB00898; DB01466; DB00574; DB12265; DB01544; DB00472; DB01095; DB00176; DB01320; DB05087; DB00986; DB01159; DB00956; DB00741; DB09054; DB01181; DB00458; DB00762; DB11633; DB06636; DB00753; DB11757; DB01167; DB14568; DB09570; DB01221; DB06738; DB01026; DB11951; DB09078; DB12070; DB05667; DB00281; DB00836; DB01601; DB00455; DB04871; DB12130; DB09280; DB00772; DB09238; DB14921; DB14009; DB01043; DB00170; DB00454; DB00532; DB04817; DB00333; DB00763; DB01028; DB09241; DB00849; DB00959; DB06710; DB00379; DB06148; DB01110; DB06595; DB16236; DB00745; DB11763; DB00220; DB00238; DB00622; DB00184; DB01115; DB04868; DB12005; DB00435; DB00957; DB09074; DB16267; DB11632; DB01173; DB11837; DB04938; DB05467; DB00715; DB08883; DB01074; DB04930; DB12978; DB03575; DB01174; DB00252; DB13941; DB17472; DB11642; DB06209; DB14631; DB00635; DB01069; DB00818; DB00908; DB00481; DB08896; DB11853; DB16826; DB02709; DB00615; DB01045; DB11753; DB01201; DB08864; DB00503; DB06176; DB00296; DB00412; DB00778; DB01037; DB06739; DB01104; DB01236; DB00641; DB00398; DB15569; DB12548; DB09118; DB06729; DB01138; DB00675; DB12020; DB12095; DB00231; DB00624; DB13943; DB13944; DB13946; DB11712; DB01041; DB09499; DB04572; DB08816; DB00208; DB06137; DB00193; DB00755; DB12245; DB12808; DB00197; DB12255; DB00313; DB11613; DB08881; DB00661; DB09185; DB11739; DB00582; DB09068; DB14975; DB15035

NA

EC 1.14.13.-

3D-structure; Alternative splicing; Endoplasmic reticulum; Heme; Iron; Lipid metabolism; Membrane; Metal-binding; Microsome; Monooxygenase; NADP; Oxidoreductase; Phosphoprotein; Proteomics identification; Reference proteome

A

53293

465

0.12

38.79

8.63

5.35

-8.11

F2R

Homo sapiens (Human)

NA

TR;PAR1;CF2R

G-protein coupled receptor 1 family

Signaling protein / antagonist

G-protein alpha-subunit binding.G-protein beta-subunit binding.G-protein coupled receptor activity.Receptor binding.Thrombin-activated receptor activity.

3-ketothiolase deficiency (3KTD) [MIM:203750]: An autosomal recessive inborn error of isoleucine catabolism characterized by intermittent ketoacidotic attacks associated with unconsciousness. Some patients die during an attack or are mentally retarded. Urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, triglylglycine, butanone is increased. It seems likely that the severity of this disease correlates better with the environmental or acquired factors than with the ACAT1 genotype. {ECO:0000269|PubMed:1346617, ECO:0000269|PubMed:1715688, ECO:0000269|PubMed:7728148, ECO:0000269|PubMed:9744475}. The disease is caused by variants affecting the gene represented in this entry.

DB05361; DB00086; DB11300; DB09030

Q03135; Q9UNN8

NA

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

A

31193.7

282

0.16

36.7

8.2

2.98

-8.12

npr

Enterococcus faecalis (strain ATCC 700802 / V583)

NA

EF_1211

Class-III pyridine nucleotide-disulfide oxidoreductase family

Oxidoreductase (h2o2(a))

Flavin adenine dinucleotide binding.NADH peroxidase activity.

Telangiectasia, hereditary hemorrhagic, 2 (HHT2) [MIM:600376]: A multisystemic vascular dysplasia leading to dilation of permanent blood vessels and arteriovenous malformations of skin, mucosa, and viscera. The disease is characterized by recurrent epistaxis and gastro-intestinal hemorrhage. Visceral involvement includes arteriovenous malformations of the lung, liver, and brain. {ECO:0000269|PubMed:10694922, ECO:0000269|PubMed:10767348, ECO:0000269|PubMed:11170071, ECO:0000269|PubMed:11484689, ECO:0000269|PubMed:14684682, ECO:0000269|PubMed:15024723, ECO:0000269|PubMed:15712270, ECO:0000269|PubMed:16525724, ECO:0000269|PubMed:16752392, ECO:0000269|PubMed:20414677, ECO:0000269|PubMed:26176610, ECO:0000269|PubMed:8640225, ECO:0000269|PubMed:9245985}. The disease is caused by variants affecting the gene represented in this entry.

DB03147; DB03382

NA

1.11.1.1

3D-structure; Direct protein sequencing; FAD; Flavoprotein; NAD; Oxidation; Oxidoreductase; Peroxidase; Redox-active center; Reference proteome

A

49518.8

447

0.09

27.53

4.83

-19.06

-8.11