A guide to the effects of a large portion of the residues of triosephosphate isomerase on catalysis, stability, druggability, and human disease

Abstract

Triosephosphate isomerase (TIM) is a ubiquitous enzyme, which appeared early in evolution. TIM is responsible for obtaining net ATP from glycolysis and producing an extra pyruvate molecule for each glucose molecule, under aerobic and anaerobic conditions. It is placed in a metabolic crossroad that allows a quick balance of the triose phosphate aldolase produced by glycolysis, and is also linked to lipid metabolism through the alternation of glycerol-3-phosphate and the pentose cycle. TIM is one of the most studied enzymes with more than 199 structures deposited in the PDB. The interest for this enzyme stems from the fact that it is involved in glycolysis, but also in aging, human diseases and metabolism. TIM has been a target in the search for chemical compounds against infectious diseases and is a model to study catalytic features. Until February 2017, 62% of all residues of the protein have been studied by mutagenesis and/or using other approaches. Here, we present a detailed and comprehensive recompilation of the reported effects on TIM catalysis, stability, druggability and human disease produced by each of the amino acids studied, contributing to a better understanding of the properties of this fundamental protein. The information reviewed here shows that the role of the noncatalytic residues depend on their molecular context, the delicate balance between the short and long-range interactions in concerted action determining the properties of the protein. Each protein should be regarded as a unique entity that has evolved to be functional in the organism to which it belongs. Proteins 2017; 85:1190-1211. © 2017 Wiley Periodicals, Inc.

Structural basis for the modulation of plant cytosolic triosephosphate isomerase activity by mimicry of redox‐based modifications

“…We mutated AtcTPI‐Cys218 to Met, Val, and Lys that resemble the conjugation to linear adducts like MMTS or S ‐glutathionylation and to Tyr because this modification would resemble the chemical conjugation to a bulky aromatic adduct line DTNB, and finally to aspartic acid that mimics its oxidation to sulfinic acid. We did not mutate residue AtcTPI‐Cys13 to bulky amino acids like Tyr or Lys, because amino acids with larger side chains are not present at this position in any TPI reported to date and because the large van der Waals radius of these residues would hamper dimer formation (Lara‐Gonzalez et al ., ; Olivares‐Illana et al ., ) (Figure a).…”

“…The crystal structure of AtcTPI shows that the thiol groups of residues Cys13 and Cys218 are solvent exposed, whereas the thiol groups of residues Cys67 and Cys127 are completely buried (Figure a) (López‐Castillo et al ., ). The identity of residue 127 corresponds to a cysteine in all TPIs known to date (Olivares‐Illana et al ., ) and its glutathionylation is unforeseen, as the thiol group of this residue is always buried. Mutations of cysteine 127 decrease thermal stability and dimer association, revealing that this residue is critical to stabilize the dimer interface by interacting with amino acids that assemble this interface (Gonzalez‐Mondragon et al ., ; Samanta et al ., ).…”

Crystal structures of Triosephosphate Isomerases from Taenia solium and Schistosoma mansoni provide insights for vaccine rationale and drug design against helminth parasites

“…TPIs exhibit a similar length in their secondary structural elements and are not prone to insertions or deletions [53]. TsTPI and SmTPI share 59% amino acid identity and a distinctive feature is the presence of a region of three amino acids, (S155 to E157 and S157 to D159, in TsTPI and SmTPI, respectively) conserved among flatworms that is not present in HsTPI and nonparasitic helminths [42].…”

Potential Site to Direct Selective Compounds in the Triosephosphate Isomerase for the Development of New Drugs

“…In the pharmaceutical industry, the development of selective drugs to an enzyme or the repositioning of commercial drugs, today, is booming. The glycolytic enzyme triosephosphate isomerase (TIM) has been used as a therapeutic target for the development of new drugs against various pathogenic organisms, such as, Trypanosoma cruzi, Trypanosoma brucei, Entamoeba histolytica, Giardia duodenalis, Trichomonas vaginalis , among others . Therefore, saving resources in the development of new drugs, by directing the interaction of pharmacological compounds to a specific interaction site with a high probability to be selective, represents an opportunity, for researchers who are looking for new molecules or pharmacological compounds that they do not have a reported use, or in the case, of wanting to find another use to conventional drugs, such as omeprazole against TIM [11] [12] .…”

“…In this study, we propose a potential site as a therapeutic target against the enzyme triosephosphate isomerase for drug development, and that this potential new drug could be safe to be used at humans. We determined the K in position 214 (near the sequence YGGSV−K214) is indispensable for the interaction with the tested compounds and it helps the interaction in the active site from TIM.…”