Bifunctional purine biosynthesis protein ATIC (ATIC)
The protein contains 592 amino acids for an estimated molecular weight of 64616 Da.
Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis (PubMed:11948179, PubMed:14756554). Acts as a transformylase that incorporates a formyl group to the AMP analog AICAR (5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide) to produce the intermediate formyl-AICAR (FAICAR) (PubMed:9378707, PubMed:11948179, PubMed:10985775). Can use both 10-formyldihydrofolate and 10-formyltetrahydrofolate as the formyl donor in this reaction (PubMed:10985775). Also catalyzes the cyclization of FAICAR to IMP (PubMed:11948179, PubMed:14756554). Is able to convert thio-AICAR to 6-mercaptopurine ribonucleotide, an inhibitor of purine biosynthesis used in the treatment of human leukemias (PubMed:10985775). Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571). (updated: June 17, 2020)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology.
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| Variant | Description |
|---|---|
| dbSNP:rs2372536 | |
| AICAR |
Biological Process
'de novo' IMP biosynthetic process
Animal organ regeneration
Brainstem development
Cellular response to interleukin-7
Cerebellum development
Cerebral cortex development
Dihydrofolate metabolic process
Nucleobase-containing compound metabolic process
Nucleobase-containing small molecule metabolic process
Nucleoside metabolic process
Purine nucleobase metabolic process
Purine ribonucleoside monophosphate biosynthetic process
Response to inorganic substance
Small molecule metabolic process
Tetrahydrofolate biosynthetic process
The reference OMIM entry for this protein is 601731
5-@aminoimidazole-4-carboxamide ribonucleotide formyltransferase/imp cyclohydrolase; atic
Aicarft/impchase
Aicar transformylase/imp cyclohydrolase
Purh
DESCRIPTION
AICARFT (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase; EC 2.1.2.3) and IMPCHase (IMP cyclohydrolase; EC 3.5.4.10) catalyze the penultimate and final steps, respectively, of the de novo purine biosynthetic pathway (summary by Rayl et al., 1996).CLONING
Rayl et al. (1996) cloned a cDNA for human AICARFT/IMPCHase from a hepatoma cDNA library. Both enzymatic activities are present in the same protein, designated ATIC, in all species of prokaryotes and eukaryotes studied by Rayl et al. (1996). The human ATIC cDNA encodes a deduced 591-amino acid protein that is 81% identical to the chicken sequence (Ni et al., 1991). Rayl et al. (1996) created truncation mutants of the cDNA and measured their enzymatic properties. In this way they were able to localize the AICARFT activity within the amino-terminal 223 amino acids and the IMPCHase activity to the carboxyl-terminal 406 residues.MAPPING
The International Radiation Hybrid Mapping Consortium mapped the ATIC gene to chromosome 2 (TMAP RH11837).MOLECULAR GENETICS
In a 4-year-old girl who presented with dysmorphic features, severe neurologic defects, and congenital blindness and who was found to have AICA-ribosiduria (608688), Marie et al. (2004) found compound heterozygosity for mutations in the ATIC gene. Sequencing of ATIC showed a K426R mutation in the transformylase region in 1 allele (601731.0001) inherited from the father, and a frameshift mutation caused by a duplication/deletion event in the other allele (601731.0002), inherited from the mother. The missense mutation was located within a conserved region implicated in the binding of a potassium ion in the avian protein (Greasley et al., 2001). This potassium ion has been proposed to play a key role in stabilization of the tertiary structure of the protein. In expression studies, recombinant protein carrying mutation K426R completely lacked AICAR-TF activity but still showed IMP-CH activity. The presence of massive amounts of AICA-riboside in the patient's urine and the accumulation of AICAR (also referred to as ZMP) and its derivatives in her erythrocytes and fibroblasts were taken by Marie et al. (2004) to be a clear indication of deficiency in the enzyme that utilizes this intermediate de novo purine biosynthesis, the bifunctional enzyme AICAR transformylase/IMP cyclohydrolase. ... More on the omim web site
June 29, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 5, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 601731 was added.
Jan. 27, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed