Alternative titles; symbols
HGNC Approved Gene Symbol: GAPDH
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:6,534,517-6,538,371 (from NCBI)
Glyceraldehyde-3-phosphate dehydrogenase (EC 1.2.1.12) catalyzes an important energy-yielding step in carbohydrate metabolism, the reversible oxidative phosphorylation of glyceraldehyde-3-phosphate in the presence of inorganic phosphate and nicotinamide adenine dinucleotide (NAD) (Dayhoff, 1972).
Sequence data for GAPD were published in the atlas of Dayhoff (1972). The enzyme is present in such widely separated forms as man, lobster, and E. coli. Its rate of evolutionary change is one of the slowest known. In the cytoplasm GAPDH exists primarily as a tetrameric isoform composed of 4 identical 37-kD subunits. GAPDH is also found in the particulate fractions, such as the nucleus, the mitochondria, and the small vesicular fractions (review by Tristan et al., 2011).
Variants have been found in a number of phyletically diverse organisms (Lebherz and Rutter, 1967). as in lactic acid dehydrogenase. Variants were found in man by Charlesworth (1972).
Burke et al. (1996) demonstrated that synthetic polyglutamine peptides, DRPLA protein (607462) and huntingtin (HTT; 613004) from unaffected individuals with normal-sized polyglutamine tracts bind to GAPD. They noted that GAPD has also been shown to bind to RNA, ATP, calcyclin (114110), actin (see 102610), tubulin (see 191130) and amyloid precursor protein (104760). On the basis of their findings, Burke et al. (1996) postulated that the diseases characterized by the presence of an expanded CAG repeat may share a common metabolic pathogenesis involving GAPD as a functional component. Roses (1996) and Barinaga (1996) reviewed the findings.
Using human embryonic kidney and mouse neuroblastoma cell lines, Bae et al. (2006) showed that nuclear translocation and associated neurotoxicity of mutant huntingtin was mediated by a ternary complex of huntingtin, GAPDH, and SIAH1 (602212), a ubiquitin E3 ligase that provided the nuclear translocation signal. Overexpression of GAPDH or SIAH1 enhanced nuclear translocation of mutant huntingtin and cytotoxicity, whereas GAPDH mutants unable to bind SIAH1 prevented translocation. Depletion of GAPDH or SIAH1 by RNA interference diminished nuclear translocation of mutant huntingtin.
Zheng et al. (2003) isolated and functionally characterized a multicomponent OCT1 (164175) coactivator, OCAS, that is essential for S phase-dependent histone H2B (see 609904) transcription. The p38 component of OCAS, which the authors identified as GADPH, bound directly to OCT1, exhibited potent transactivation potential, was selectively recruited to the H2B promoter in S phase, and was essential for S phase-specific H2B transcription in vivo and in vitro. Binding to OCT1, as well as OCAS function, was stimulated by NAD+, but inhibited by NADH. OCAS also interacted with NPAT (601448), a cyclin E (123837)/CDK2 (116953) substrate broadly involved in histone gene transcription. These studies linked the H2B transcriptional machinery to cell cycle regulators, and possibly to cellular metabolic state (redox status), and set the stage for studies of the underlying mechanisms and the basis for coordinated histone gene expression and coupling to DNA replication.
Meyer-Siegler et al. (1991) isolated a cDNA for uracil-DNA glycosylase (see UNG; 191525) that, to their surprise, was completely homologous to the 37-kD subunit of GAPD. They showed that the 37-kD subunit of commercially obtained erythrocyte GAPD possessed uracil-DNA glycosylase activity comparable to that seen for the purified human placental enzyme. However, Caradonna et al. (1996) were unable to replicate the work of Meyer-Siegler et al. (1991). They found that commercially available human erythrocyte GAPDH showed no uracil-DNA glycosylase activity.
Laschet et al. (2007) showed that GAPDH also acts as a kinase involved in the glycolysis-dependent endogenous phosphorylation of the alpha-1 subunit of the GABA-A receptor (GABRA1; 137160), a mechanism that is necessary for maintaining GABA-A receptor function.
In apoptotic cells, mitochondrial outer membrane permeabilization (MOMP) is followed by caspase activation promoted by released cytochrome c (see CYCS; 123970). Caspase inhibition is usually not sufficient for survival after MOMP, and instead cells undergo caspase-independent cell death (CICD). Colell et al. (2007) found that GAPDH-expressing cells preserved their clonogenic potential following MOMP if caspase activation was also blocked. GAPDH-mediated protection from CICD was accompanied by elevated glycolysis and an increase in ATG12 (609608) expression. Electron and confocal microscopy and flow cytometric analysis demonstrated that protection from CICD was associated with an increase in and dependence on autophagy, as well as a transient decrease in mitochondrial mass. Colell et al. (2007) concluded that GAPDH mediates an elevation in glycolysis and enhanced autophagy that cooperate to protect cells from CICD.
Using proteomic techniques, ELISA, and Western blot analysis, Mookherjee et al. (2009) identified GAPDH as a direct binding partner for LL37 (CAMP; 600474), a cationic host defense peptide, in human monocytes. Enzyme kinetics and mobility shift studies also showed that LL37 and its synthetic counterpart, IDR1, bound to GAPDH. Silencing of GAPDH impaired p38 MAPK (MAPK14; 600289) signaling and p38 MAPK-dependent chemokine and cytokine responses. Mookherjee et al. (2009) concluded that GAPDH is a mononuclear cell receptor for LL37 and is involved in the functioning of cationic host defense peptides.
N-methyl-D-aspartate (NMDA) stimulation of rodent cerebellar granule neurons elicits nitric oxide generation, followed by S-nitrosylation of Gapdh, binding between Gapdh and Siah, Siah-mediated nuclear translocation of Gapdh, and neurotoxicity. Sen et al. (2009) found that rat Gospel (RILPL1; 614092) bound the N-terminal region of Gapdh and competed with Siah for Gapdh binding, thereby preventing Gapdh nuclear translocation. S-nitrosylation of Gospel was required for binding to Gapdh, as a Gospel mutant unable to be S-nitrosylated was not neuroprotective. Overexpression of Gospel reduced nuclear accumulation of Gapdh in HEK293 and mouse cortical neuron cultures and reduced NMDA-glutamate neuronal excitotoxicity. Conversely, depletion of Gospel by RNA interference enhanced Gapdh nuclear accumulation and cell death in primary neuron cultures.
IFN-gamma (IFNG; 147570) induces ribosome release of RPL13A (619225) and assembly of RPL13A into the IFN-gamma-activated inhibitor of translation (GAIT) complex, which mediates translational control of a subset of inflammatory-related proteins. Jia et al. (2012) found that oxidatively modified low density lipoprotein (LDLox) suppressed GAIT-mediated translational control by selectively degrading RPL13A and preventing formation of an active, mature GAIT complex in human myeloid cells. Phosphorylation of RPL13A was required for its recognition and degradation by the ubiquitylation system. GAPDH functioned as a chaperone for newly released phosphorylated RPL13A by binding it and shielding it from proteasomal degradation. However, LDLox S-nitrosylated GAPDH, which inactivated the protective function of GAPDH, leading to ubiquitylation and degradation of phosphorylated RPL13A and loss of GAIT complex activity.
Activated immune cells undergo a metabolic switch to aerobic glycolysis akin to the Warburg effect, thereby presenting a potential therapeutic target in autoimmune disease. Dimethyl fumarate (DMF), a derivative of the Krebs cycle intermediate fumarate, is an immunomodulatory drug used to treat multiple sclerosis and psoriasis. DMF covalently modifies cysteine residues in a process termed succination. Kornberg et al. (2018) found that DMF succinates and inactivates the catalytic cysteine of the glycolytic enzyme GAPDH in mice and humans, both in vitro and in vivo. It thereby downregulates aerobic glycolysis in activated myeloid and lymphoid cells, which mediates its antiinflammatory effects. Kornberg et al. (2018) concluded that their results provided mechanistic insight into immune modulation by DMF and represented a proof of concept that aerobic glycolysis is a therapeutic target in autoimmunity.
Yang et al. (2018) showed that GAPDH inhibited coat protein I (COPI; see 601924) transport by targeting a GTPase-activating protein towards ADP-ribosylation factor-1 (ARF1; 103180) to suppress COPI vesicle fission. GAPDH inhibited multiple other transport pathways, also by targeting ARF GAPs. Further characterization suggested that this broad inhibition is activated by the cell during starvation to reduce energy consumption. Yang et al. (2018) concluded that their findings revealed a remarkable level of coordination among the intracellular transport pathways that underlies a critical mechanism of cellular energy homeostasis.
Several groups, including Myers et al. (2002), have reported linkage on chromosome 12 in late-onset Alzheimer disease (LOAD; 104300) families. To follow up on these results, Li et al. (2004) genotyped 282 single-nucleotide polymorphisms (SNPs) under the linkage peak which their group had previously identified, studying a multiple case-control series totaling 1,089 AD subjects and 1,196 non-demented controls. A strong association was observed in a small region chromosome 12 that includes the GAPD gene, which led them to examine this gene and its paralogs on other chromosomes. These studies showed association with 2 other paralogs: GAPD2 on chromosome 19 (609169), and a GAPD pseudogene on chromosome 12q. A significant association between LOAD and a compound genotype of 3 GAPD genes was observed in all 3 sample sets. Individually these SNPs made differential contributions to disease risk in each of the case-control series, suggesting that variants in functionally similar genes may account for series-to-series heterogeneity of disease risk. In general, the observations raised the possibility that the GAPD genes are AD risk factors, a hypothesis that is consistent with the role of GAPD in neuronal apoptosis.
Lin et al. (2006) found no association between 12 SNPs in the GAPD gene and its paralogs and family-based Alzheimer disease among 235 AD families.
By study of somatic cell hybrids, Bruns and Gerald (1976) showed that a gene specifying GAPD is syntenic with the genes specifying TPI (190450) and LDHB (150100) and therefore is on chromosome 12. Hence, 3 genes specifying enzymes involved in the Embden-Meyerhof glycolytic pathway are on the same chromosome. Six other enzymes of the pathway have been assigned to other chromosomes. Edwards et al. (1976) discussed the inconclusive evidence for more than one locus for GAPD. Studying the level of enzyme in 2 cases of partial trisomy and in one of partial monosomy of the short arm of chromosome 12, Rethore et al. (1976) concluded that GAPD is located on the distal part of 12p between 12p12.2 and 12pter, and that the LDHB locus is on the middle third between 12p12.1 and 12p12.2. The results for TPI were similar to those for GAPD, suggesting the same distal localization.
By gene dosage effects, Serville et al. (1978) assigned TPI and GAPD to the distal end of 12p (12p13). Law and Kao (1978) summarized data suggesting the order 12pter--TPI--GAPD--SHMT on chromosome 12. SHMT lies on the proximal part of 12q between the centromere and PEPB. By dosage effect in a case of deletion, Rivas et al. (1985) narrowed the assignment to 12p13.1-12p13.31. Benham and Povey (1989) confirmed the presence of a single expressed locus for this major glycolytic enzyme on 12p13. They also confirmed the existence of a pseudogene mapping to Xp21-p11 and identified 15 GAPD-like loci by use of reduced stringency.
Pseudogenes
Like GLUDP1 (see 138130), the first probe isolated for glyceraldehyde-3-phosphate dehydrogenase (symbolized GAPDP1) represented a pseudogene on the X chromosome. The functional gene, GAPD, is located in band 12p13. At HGM8, the pseudogene was assigned to Xp21-p11 on the basis of in situ hybridization studies in several laboratories (Goodfellow et al., 1985).
Li et al. (2004) located a GAPD pseudogene on chromosome 12q.
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