Understanding human thiol dioxygenase enzymes: structure to function, and biology to pathology

Abstract

Amino acid metabolism is a significant metabolic activity in humans, especially of sulphur-containing amino acids, methionine and cysteine (Cys). Cys is cytotoxic and neurotoxic in nature; hence, mammalian cells maintain a constant intracellular level of Cys. Metabolism of Cys is mainly regulated by two thiol dioxygenases: cysteine dioxygenase (CDO) and 2-aminoethanethiol dioxygenase (ADO). CDO and ADO are the only human thiol dioxygenases reported with a role in Cys metabolism and localized to mitochondria. This metabolic pathway is important in various human disorders, as it is responsible for the synthesis of antioxidant glutathione and is also for the synthesis of hypotaurine and taurine. CDO is the most extensively studied protein, whose high-resolution crystallographic structures have been solved. As compared to CDO, ADO is less studied, even though it has a key role in cysteamine metabolism. To further understand ADO's structure and function, the three-dimensional structures have been predicted from I-TASSER and SWISS-MODEL servers and validated with PROCHECK software. Structural superimposition approach using iPBA web server further confirmed near-identical structures (including active sites) for the predicted protein models of ADO as compared to CDO. In addition, protein-protein interaction and their association in patho-physiology are crucial in understanding protein functions. Both ADO and CDO interacting partner profiles have been presented using STRING database. In this study, we have predicted a 3D model structure for ADO and summarized the biological roles and the pathological consequences which are associated with the altered expression and functioning of ADO and CDO in case of cancer, neurodegenerative disorders and other human diseases.

The Evaluation of Glutathione Reductase and Malondialdehyde Levels in Patients With Lumbar Disc Degeneration Disease

“…These reactions convert GSH to GSSG by means of glutathione peroxidase. GSSG, in turn, is converted to GSH by glutathione reductase (10,11,27). Antioxidant GSSG molecule receives reducing equivalents in a variety of chemical mitochondrial redox system and forms glutathione/oxidized glutathione (GSH/GSSG) system.…”

“…Glutathione protects the cell against the noxious effects of oxidized molecules with the -SH groups in its structure. The main functions of glutathione include: i) detoxification of free radicals and reactive oxygen species (ROS) in the cell, ii) protection of thiol moieties in various enzymes and membrane proteins, such as hemoglobin and spectrin iii) synthesis of DNA and proteins, iv) conjugation of xenobiotics, some antineoplastic drugs, and some metabolic end products for detoxification, v) transport of amino acids, vi) cleavage of disulfide bonds of insulin and some other proteins, leading to alterations in the conformation of their protein structures, vii) storage of intracellular cysteine, and viii) involvement in several enzymatic reactions (9)(10)(11). Because these are critical tasks, metabolic impairment may occur due to low intracellular concentration of glutathione (12).…”

Leishmania infantum 5’-Methylthioadenosine Phosphorylase presents relevant structural divergence to constitute a potential drug target

“…For this purpose, 3D models of the parasite MTAPs were performed by I-TASSER, matching structure predictions with known functional templates [ 41 ]. This homology modeling server was already used by other groups for instance to understand functions of human thiol dioxygenase enzymes [ 63 ] and to assess stability of the Rabies Virus G protein trimer through molecular dynamics [ 64 ].…”

Genetics of Behçet’s Disease

“…Two genetic loci between the ADO and the EGR2 genes and the CEBPB and the PTPN1 genes were associated with BD in the Turkish, Iranian, and Japanese cohorts [78]. The ADO encodes cysteamine (2-aminoethanethiol) dioxygenase that is involved in amino acid metabolism [139]. The EGR2 encodes early growth response protein 2 that is a transcription factor, and highly expressed in a population of migrating neural crest cells [140].…”