The human alpha class genes are located in a cluster on chromosome 6p12 and comprise five functional genes (GSTA1, GSTA2, GSTA3, GSTA4, GSTA5) and seven pseudogenes (Morel et al., 2002).

The GSTA1 gene is approximately 12 kb in length and is closely flanked by other alpha class gene sequences. The complete sequence of the 1,7-kb intergenic region between exon 7 of an upstream pseudogene and exon 1 of the GSTA1 gene has been determined (Suzuki et al., 1993).

The 1276-nucleotide transcript encodes a protein of 222 amino acid residues.

An additional gene that encodes an uncharacterized Alpha class GST has been identified. The protein derived from this gene would have 19 amino acid substitutions compared with the GSTA1 isoenzyme. Several pseudogenes with single-base and/or complete exon deletions have been identified, but no reverse-transcribed pseudogenes have been detected (Suzuki et al., 1993).
Polymorphisms: GSTA1 has a functional three apparently linked single nucleotide polymorphisms (SNPs) in an SP1-responsive element within the proximal promoter (G-52A, C-69T and T-567G), plus at least four SNPs further upstream and a silent SNP A-375G. Two variants, GSTA1*A (-567T, -69C,-52G) and GSTA1*B (-67G, -69T, -52A), have been named according to the linked functional SNPs. Specifically, these substitutions result in differential expression with lower transcriptional activation of variant GSTA1*B than common GSTA1*A allele. It has been suggested that this genetic variation can change an individuals susceptibility to carcinogens and toxins, as well as, affect the efficacy of some drugs (Coles and Kadlubar, 2003). In addition, the linkage disequilibrium between GSTA1*A/GSTA1*B and GSTA2G335C (Ser112Thr) has been shown in Caucasians: specifically, GSTA1*A/GSTA2C335 (Thr112) and GSTA1*B/GSTA2G335 (Ser112) (Ning et al., 2004). It seems that the higher hepatic expression of GSTA1 enzyme in homozygous GSTA1 individuals is associated with the lower hepatic expression of GSTA2 in GSTA2C335 (Thr112) individuals (Coles et al., 2001a; Ning et al., 2004). Other haplotypes within this nomenclature but including SNPs C-115T, T-631G, and C-1142G also have been proposed (Bredschneider et al., 2002; Guy et al., 2004). Polymorphisms upstream of G-52C seem to have little effect on GSTA1 expression (Morel et al., 2002).

Glutathione S-transferase A1 is N-terminally processed.
Amino acids: 222.
Calculated molecular mass: 25,63 kDa.

The active GSTA1-1 enzyme is a homodimer, with each subunit containing a GSH-binding site (G-site) and a second adjacent hydrophobic binding site for the electrophilic substrate (H-site) (Wilce and Parker, 1994). The C-terminal region of GSTA1-1 contributes to the catalytic and noncatalytic ligand-binding functions of the enzyme, while the conserved G-site is located in the N-terminal domain (Balogh et al., 2009). Protein flexibility and dynamics in a molten globule-active site including the C-terminal α9 helix and the protruding ends of the α4-α5 helices result in achieving remarkable catalytic promiscuity of GSTA1-1 (Wu and Dong, 2012; Honaker et al., 2013). It has been proposed that the α9 helix may function as a mobile gate to the active-site cavity, controlling substrate access and product release.

GSTA1-1 is highly expressed (as mRNA and protein) in liver, intestine, kidney, adrenal gland, pancreas and testis, while expression in a wide range of tissues is low (Hayes and Pulford, 1995; Coles et al., 2001a). Both positive and negative regulatory regions are present in the 5` noncoding region of GSTA1, including a polymorphic SP1-binding site within the proximal promoter. Binding of the transcription factor AP1 has been suggested as a common mechanism for up-regulation of GSTs (Hayes and Pulford, 1995). The results of recent study also implied the role of a Kelch-like ECH-associated protein 1 (Keap1)-dependent signaling pathway for the induction of the constitutive GSTA1 expression during epithelial cell differentiation (Kusano et al., 2008). Regarding GSH-dependent Δ⁵-Δ⁴ isomerase activity of this class of enzyme, it has been shown that steroidogenic factor 1 (SF-1) is involved in regulation of expression of GSTA genes (Matsumura et al., 2013). Aberrant overexpression has been observed in various malignancies such as colorectal (Hengstler et al., 1998) and lung cancer (Carmichael et al., 1988), while decrease in alpha class GSTs has been observed in stomach and liver tumors (Howie et al., 1990). A detailed recent review on GSTA1 can be found in Wu and Dong, 2012.

Cytosolic.

Human GSTA1-1 enzyme catalyzes the GSH-dependent detoxification of electrophiles showing highly promiscuous substrate selectivity for many structurally unrelated chemicals, including environmental carcinogens (e.g. benzo(a)pyrene diol epoxides), several alkylating chemotherapeutic agents (such as busulfan, chlorambucil, melphalan, phosphoramide mustard, cyclophosphamide, thiotepa), as well as, steroids and products of lipid degradation. GSTA1-1 is the most highly expressed GST of the liver and could therefore, be critical for "systemic" detoxification of electrophilic xenobiotics including carcinogens and drugs (Coles and Kadlubar, 2005). In addition to enzymatic detoxification, GSTA1 acts as modulator of mitogen-activated protein kinase (MAPK) signal transduction pathway via a mechanism involving protein-protein interactions. Namely, GSTA1 forms complexes with c-Jun N-terminal kinase (JNK), modifying JNK activation during cellular stress (Adnan et al., 2012). Thus, it is possible that GSTA1 confer drug resistance by two distinct means: by direct inactivation (detoxification) of chemotherapeutic drugs and by acting as inhibitors of MAPK pathway.

The alpha class GSTs is showing strong intra-class sequence similarity (Balogh et al., 2009).

None described so far.

36 mutations (COSMIC): 26 substitution-missense, 4 substitution-nonsense, 5 substitution-coding silent, 1 unknown type.