Mannose-1-phosphate guanyltransferase alpha (GMPPA)
The protein contains 420 amino acids for an estimated molecular weight of 46291 Da.
May serve as a regulatory subunit and allow allosteric feedback inhibition of GMPPB by GDP-mannose. (updated: March 4, 2015)
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.
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| Variant | Description |
|---|---|
| dbSNP:rs34218609 | |
| dbSNP:rs13396066 | |
| AAMR | |
| AAMR | |
| AAMR | |
| AAMR | |
| AAMR; drastically reduced protein expression |
The reference OMIM entry for this protein is 615495
Gdp-mannose pyrophosphorylase a; gmppa
Gdp-mannose pyrophosphorylase, alpha subunit
Gmpp-alpha
DESCRIPTION
GMPPA is a homolog of GDP-mannose pyrophosphorylase B (GMPPB; 615320), which catalyzes the synthesis of GDP-mannose from mannose-1-phosphate and GTP. GMPPA and GMPPB are present in roughly equal amounts in native GDP-mannose pyrophosphorylase (EC 2.7.7.13), but only GMPPB exhibits enzymatic activity. Compared with GMPPB, GMPPA has a 2-amino acid insertion within a highly conserved nucleotide-binding motif that likely inactivated it after the duplication event that produced GMPPA and GMPPB. GMPPA may serve a regulatory role for GMPPB (Koehler et al., 2013).CLONING
Koehler et al. (2013) identified the GMPPA gene within a region of chromosome 2 linked to alacrima, achalasia, and mental retardation syndrome (AAMR; 615510). The deduced GMPPA protein contains 420 amino acids. It has a predicted N-terminal nucleotidyltransferase domain followed by a hexapeptide repeat domain. GMPPA shares 32% amino acid identity with GMPPB. Northern blot analysis detected variable Gmppa expression in all 17 mouse tissues examined, with highest expression in adrenal gland and testis, and lowest expression in lung and spleen. In situ hybridization of day-17.5 mouse embryo found Gmppa expression in many tissues, including cortex, stomach, intestine, submandibular gland, and sublingual gland. Epitope-tagged human GMPPA was expressed in a diffuse cytoplasmic pattern in transfected COS-7 cells. Database analysis revealed orthologs of GMPPA in mammals and fish, and all had the inactivating 2-amino acid insertion compared with GMPPB.GENE FUNCTION
Koehler et al. (2013) stated that GMPPA binds GDP-mannose, but that it does not show catalytic activity.MAPPING
Hartz (2013) mapped the GMPPA gene to chromosome 2q35 based on an alignment of the GMPPA sequence (GenBank GENBANK AF135422) with the genomic sequence (GRCh37).MOLECULAR GENETICS
In 13 patients from 9 unrelated families with alacrima, achalasia, and mental retardation syndrome (AAMR; 615510), Koehler et al. (2013) identified 9 different homozygous mutations in the GMPPA gene (see, e.g., 615495.0001-615495.0005). The mutation in the first family was found by linkage analysis and whole-exome sequencing. The subsequent mutations were identified by sequencing the GMPPA gene in 63 families with alacrima and achalasia who were negative for mutations in the AAAS gene (605378). Immunoblot analysis of patient cells with missense mutations showed lower levels of GMPPA compared to controls, consistent with a loss of function. However, GDP-mannose levels were significantly higher in patient cells compared to controls, whereas other nucleotide diphosphate sugars were unchanged. There was no evidence of alterations in N-glycosylation profiles in patients: serum transferrin, immunoglobulin G, and serum Apo-CIII glycosylation profiles were similar to those in controls. Koehler et al. (2013) suggested that changes induced by GDP-mannose overload might only be significant in restricted cell types or affect other glycosylation types, or may lead to perturbations in the levels of other guanine nucleotides. Alternatively, GMPPA might serve as a regulatory subunit. The clinical features of the patients with mutations indicated that GMPPA is important in neurons and autonomic nerve fibers innervating the distal esophageal sphincter or the lacrimal glands. ... More on the omim web site
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 615495 was added.