Biology:GSTZ1

Generic protein structure example

Glutathione S-transferase Zeta 1 (also known as maleylacetoacetate isomerase) is an enzyme that in humans is encoded by the GSTZ1 gene on chromosome 14.

This gene is a member of the glutathione S-transferase (GSTs) super-family, which encodes multifunctional enzymes important in the detoxification of electrophilic molecules, including carcinogens, mutagens, and several therapeutic drugs, by conjugation with glutathione. This enzyme also plays a significant role in the catabolism of phenylalanine and tyrosine. Thus, defects in this enzyme may lead to severe metabolic disorders, including alkaptonuria, phenylketonuria and tyrosinaemia, and new discoveries may allow the enzyme to protect against certain diseases related to oxidative stress.

Structure

Glutathione S-transferase Zeta 1 (GSTZ1) has a predominantly hydrophobic dimer, just like many other GST members. It is composed of 24.2 kDa subunits and it consists of an N-terminal thioredoxin-like domain and a C-terminal all alpha-helical domain. Both of these domains are intertwined by a linker region between amino acids 85 and 91. The active site of this enzyme is much smaller and more polar than that of other family members of GST, which allows for GSTZ1 to be more selective in terms of substrates. Also, the C-terminus is truncated and the GSTZ1 enzyme lacks the normal V-shaped dimer interface which are usually common in other GSTs. As for the GSTZ1 gene, it is located on chromosome 14q24.3, has 12 exons, and is approximately 10 kb long. GSTZ1 also contains a distinct motif (Ser14–Ser15–Cys16) which is seen as the active center in catalysis.

Function

GSTZ1 is predominantly found in liver cells; more specifically, it is localized in both the cytosol and the mitochondria. GSTZ1 is essentially known for catalyzing glutathione-dependent isomerization of maleylacetoacetate to fumarylacetoacetate, which is the second-to-last step in the vital phenylalanine and tyrosine degradation pathway. It is the only enzyme in the GST family that catalyses a significant process in intermediary metabolism and it ensures that this enzyme can be found in a variety of species from humans to bacteria. Another function of the GSTZ1 is that it is in control of the biotransformation of alpha-haloacids, like dichloroacetic acid (DCA), to glyoxylic acid. This prevents the buildup of DCA, which can lead to asymptomatic hepatotoxicity and a reversible peripheral neuropathy. Both functions for this enzyme requires the presence of glutathione (GSH) in order to work.

Clinical Significance

Deficiencies in any of the enzymes in the catabolism of phenylalanine and tyrosine, like GSTZ1, has led to diseases such as alkaptonuria, phenylketonuria, and several forms of tyrosinemia. A lack of GSTZ1, specifically, leads to the amalgamation of maleylacetoacetate and succinylacetone which has been observed to cause oxidative stress. Also, scarcities have been seen to alter the metabolism of certain drugs and xenobiotics in mice.

Most importantly, researchers have successfully genetically engineered GSTZ1 to mimic one of the most significant antioxidant enzymes, glutathione peroxidase (GPX). GPX is most known for its role to protect cells and tissues against oxidative damage by catalyzing the reduction of hydroperoxides using GSH as a reducing substrate and blocking the radical reaction caused by lipid peroxides. By protecting against this oxidative damage, GPX essentially prevents against degenerative diseases such as atherosclerosis, myocardial ischemia, heart failure, diabetes, pulmonary fibrosis, neurodegenerative disorders, and Alzheimer’s disease. However, because of GPX’s poor stability and paucity, it cannot be used in clinical studies and other methods must be considered. The newfound seleno-hGSTZ1–1 (or the engineered GSTZ1 enzyme) has a high GPX activity and a very similar reaction mechanism to that of GPX.

Interactions

GSTZ1 has been seen to interact with:

• α-haloacids
• GSH
• Maleylacetoacetate

Further reading

• "A bird's eye view of the glutathione transferase field". Chemico-Biological Interactions 138 (1): 27–42. Oct 2001. doi:10.1016/S0009-2797(01)00277-0. PMID 11640913. 
• "Glutathione transferase zeta catalyses the oxygenation of the carcinogen dichloroacetic acid to glyoxylic acid". The Biochemical Journal. 331 331 (2): 371–4. Apr 1998. doi:10.1042/bj3310371. PMID 9531472. 
• "Glutathione transferase zeta-catalyzed biotransformation of dichloroacetic acid and other alpha-haloacids". Chemical Research in Toxicology 11 (11): 1332–8. Nov 1998. doi:10.1021/tx980144f. PMID 9815194. 
• "Characterization and chromosome location of the gene GSTZ1 encoding the human Zeta class glutathione transferase and maleylacetoacetate isomerase". Cytogenetics and Cell Genetics 83 (1–2): 109–14. 1999. doi:10.1159/000015145. PMID 9925947. 
• "Gene structure, chromosomal location, and expression pattern of maleylacetoacetate isomerase". Genomics 58 (3): 263–9. Jun 1999. doi:10.1006/geno.1999.5832. PMID 10373324. 
• "Discovery of a functional polymorphism in human glutathione transferase zeta by expressed sequence tag database analysis". Pharmacogenetics 10 (1): 49–57. Feb 2000. doi:10.1097/00008571-200002000-00007. PMID 10739172. 
• "Crystal structure of maleylacetoacetate isomerase/glutathione transferase zeta reveals the molecular basis for its remarkable catalytic promiscuity". Biochemistry 40 (6): 1567–76. Feb 2001. doi:10.1021/bi002249z. PMID 11327815. 
• "GSTZ1d: a new allele of glutathione transferase zeta and maleylacetoacetate isomerase". Pharmacogenetics 11 (8): 671–8. Nov 2001. doi:10.1097/00008571-200111000-00005. PMID 11692075. 
• "Binding and kinetic mechanisms of the Zeta class glutathione transferase". The Journal of Biological Chemistry 279 (32): 33336–42. Aug 2004. doi:10.1074/jbc.M404631200. PMID 15173170. 
• "Intronic CA-repeat and CA-rich elements: a new class of regulators of mammalian alternative splicing". The EMBO Journal 24 (11): 1988–98. Jun 2005. doi:10.1038/sj.emboj.7600677. PMID 15889141. 
• "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. Oct 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R. 
• "Polymorphisms in the human glutathione transferase zeta promoter". Pharmacogenetics and Genomics 16 (5): 307–13. May 2006. doi:10.1097/01.fpc.0000205000.07054.b3. PMID 16609361.