UBA1

Ubiquitin-like modifier activating enzyme 1
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols UBA1 ; A1S9; A1S9T; A1ST; AMCX1; GXP1; POC20; SMAX2; UBA1A; UBE1; UBE1X
External IDs OMIM: 314370 MGI: 98890 HomoloGene: 22002 GeneCards: UBA1 Gene
EC number 6.3.2.19
Orthologs
Species Human Mouse
Entrez 7317 22201
Ensembl ENSG00000130985 ENSMUSG00000001924
UniProt P22314 Q02053
RefSeq (mRNA) NM_003334 NM_001136085
RefSeq (protein) NP_003325 NP_001129557
Location (UCSC) Chr X:
47.05 – 47.07 Mb		 Chr X:
20.66 – 20.68 Mb
PubMed search

Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the UBA1 gene.[1][2] UBA1 participates in ubiquitination and the NEDD8 pathway for protein folding and degradation, among many other biological processes.[1][3] This protein has been linked to X-linked spinal muscular atrophy type 2, neurodegenerative diseases, and cancers.[4][5]

Function

The protein encoded by this gene catalyzes the first step in ubiquitin conjugation, or ubiquitination, to mark cellular proteins for degradation. Specifically, UBA1 catalyzes the ATP-dependent adenylation of ubiquitin (Ub), thereby forming a thioester bond between the two. It also continues to participate in subsequent steps of ubiquination as a Ub carrier.[4][5][6] UBA1 is one of only two human ubiquitin-activating enzymes (E1), the other being UBA6, and thus is largely responsible for protein ubiquitination in humans.[4][5][6] Through its central role in ubiquitination, UBA1 has been linked to cell cycle regulation, endocytosis, signal transduction, apoptosis, DNA damage repair, and transcriptional regulation.[4][5] Additionally, UBE1 helps regulate the NEDD8 pathway, thus implicating it in protein folding, as well as mitigating the depletion of ubiquitin levels during stress.[3]

Clinical significance

Mutations in UBA1 are associated with X-linked spinal muscular atrophy type 2.[1] UBA1 has also been implicated in neurodegenerative diseases and cancer and, thus, presents a promising a therapeutic target for inhibiting tumor growth. However, because UBA1 is involved in multiple biological processes, there are concerns that inhibiting UBA1 would also damage normal cells. Nonetheless, preclinical testing of a UBA1 inhibitor in mice with leukemia revealed no additional toxic effects to normal cells, and the success of other drugs targeting pleiotropic targets likewise support the safety of targeting UBA1 for cancer treatment[4][5] Moreover, the UBA1 inhibitors Largazole, as well as its ketone and ester derivatives, preferentially targets cancer over normal cells by specifically by blocking the ligation of Ub and UBA1 during the adenylation step of the E1 pathway. MLN4924, a NEDD8-activating enzyme inhibitor functioning according to similar mechanisms, is currently undergoing phase I clinical trials.[5]

Interactions

UBA1 has been shown to interact with:

References

  1. 1 2 3 "Entrez Gene: ubiquitin-like modifier activating enzyme 1".
  2. ↑ Kudo M, Sugasawa K, Hori T, Enomoto T, Hanaoka F, Ui M (Jan 1991). "Human ubiquitin-activating enzyme (E1): compensation for heat-labile mouse E1 and its gene localization on the X chromosome". Experimental Cell Research 192 (1): 110–7. doi:10.1016/0014-4827(91)90164-P. PMID 1845793.
  3. 1 2 Leidecker O, Matic I, Mahata B, Pion E, Xirodimas DP (Mar 2012). "The ubiquitin E1 enzyme Ube1 mediates NEDD8 activation under diverse stress conditions". Cell Cycle 11 (6): 1142–50. doi:10.4161/cc.11.6.19559. PMID 22370482.
  4. 1 2 3 4 5 6 Correale S, de Paola I, Morgillo CM, Federico A, Zaccaro L, Pallante P, Galeone A, Fusco A, Pedone E, Luque FJ, Catalanotti B (2014). "Structural model of the hUbA1-UbcH10 quaternary complex: in silico and experimental analysis of the protein-protein interactions between E1, E2 and ubiquitin". PLOS ONE 9 (11): e112082. doi:10.1371/journal.pone.0112082. PMID 25375166.
  5. 1 2 3 4 5 6 Ungermannova D, Parker SJ, Nasveschuk CG, Wang W, Quade B, Zhang G, Kuchta RD, Phillips AJ, Liu X (2012). "Largazole and its derivatives selectively inhibit ubiquitin activating enzyme (e1)". PLOS ONE 7 (1): e29208. doi:10.1371/journal.pone.0029208. PMID 22279528.
  6. 1 2 Moudry P, Lukas C, Macurek L, Hanzlikova H, Hodny Z, Lukas J, Bartek J (Apr 2012). "Ubiquitin-activating enzyme UBA1 is required for cellular response to DNA damage". Cell Cycle 11 (8): 1573–82. doi:10.4161/cc.19978. PMID 22456334.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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