Wednesday, April 27, 2011

The (Cool) Details

                TIM catalyzes the conversion of dihydroxyacetone phosphate to D-glyceraldehyde 3-phosphate in glycolysis. It has been described as a nearly perfect enzyme because its turnover rate is so fast that it is only limited by the rate of diffusion. If this enzyme is not working correctly, it is not possible 1 glucose molecule to be converted into 2 pyruvate molecules. Only half will be able to make it through the cycle. Lack-of-function mutations may occur in several locations, but the most common by far is E104D. These mutations cause a serious, progressive, neurological disorder creatively titled triose phosphate isomerase deficiency. It is characterized by chronic hemolytic anemia—the abnormal breakdown of red blood cells.

Orosz, F., Oláh, J. and Ovádi, J. (2006), Triosephosphate isomerase deficiency: Facts and doubts. IUBMB Life, 58: 703–
715. doi: 10.1080/15216540601115960

TIM is made up of two hemolytic dimers. The protein is only functional as a dimer. The active site is located at the interface of the two monomers; however, the residues involved in binding are only on one of the monomers. The active site is buried in the center of the protein to exclude solvent. The buried active site stabilizes an enediolate intermediate.

Wierenga, R K., E G. Kapetaniou, and R Venkatesan. "Triosephosphate isomerase: a highly evolved biocatalyst." Cell Mol Life Sci67.237 Aug. (2010): 3961-82. Medline. Web. 28 Apr. 2011.

Trypanosoma brucei, the parasites that cause African sleeping sickness, have a unique 22-amino acid fragment that is buried in their triose phosphate isomerase enzymes. This amino acid fragment is capable of sending out a reporter protein to the glycosomes (a subgroup of peroxisomes). Triose phosphate isomerase is found almost exclusively in the cytosol. Mutations of similar organisms containing the fragment did not target the glycosomes. This presents a potential drug target for African sleeping sickness.

Galland, N., de Walque, S., Voncken, F.G., Verlinde, C.L., Michels, P.A. “An internal sequence targets Trypanosoma brucei triosephosphate isomerase to glycosomes” Mol Biochem Parasitol 171.1 May (2010): 45-49. Medline. Wed. 28 Apr. 2011.

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