Disease relevance of Tb10.70.5800

• Hexokinase is the first enzyme involved in glycolysis in most organisms, including the etiological agents of Chagas disease (Trypanosoma cruzi) and African sleeping sickness (Trypanosoma brucei) [1].
• Knockdown of hexokinase rescued PEX14 knockdown cells from glucose toxicity, even though glycosomal proteins continue to be mislocalized to the cytosol [2].

High impact information on Tb10.70.5800

• Probing the role of compartmentation of glycolysis in procyclic form Trypanosoma brucei: RNA interference studies of PEX14, hexokinase, and phosphofructokinase [2].
• We subsequently found that silencing of hexokinase, a glycolytic enzyme, also yielded tubercidin-resistant parasites [3].
• This biphasic relation could be related to the large difference between the affinities of the glucose transporter and hexokinase for intracellular glucose [4].
• No evidence was found for direct channeling of the ATP generated by glycerol kinase and either hexokinase or phosphofructose kinase in glycosomal enzyme complexes cross-linked by dimethyl suberimidate treatment of intact glycosomes prior to solubilization of their membrane [5].
• The purified glycosomes have 11 major proteins, 6 of which, tentatively identified as phosphofructose kinase, hexokinase, 3-phosphoglycerate kinase, aldolase, glyceraldehyde-3-phosphate dehydrogenase, and alpha-glycerophosphate dehydrogenase, constitute 87% of the total glycosomal protein [6].

Biological context of Tb10.70.5800

• Hexokinase, the first enzyme of the glycolytic pathway, was chosen as a target for selective drug design [7].
• Glucose is not concentrated internally but is taken up by facilitated diffusion, while phosphorylation by hexokinase is probably the rate-limiting step for glucose metabolism [8].
• At each steady state (specific growth rate, mu, equals D, the dilution rate), the following parameters were measured: external glucose concentration (Glcout), cell density, dry weight, protein, internal glucose concentration (Glcin), cellular ATP level, and hexokinase activity [8].

Anatomical context of Tb10.70.5800

• The compound most active against T. cruzi hexokinase was found to have a 2.2 microM IC(50) versus the clinically relevant intracellular amastigote form of T. cruzi, but only a approximately 1-2 mM IC(50) versus Dictyostelium discoideum and a human cell line, indicating selective activity versus T. cruzi [1].
• Again, substantial fumarate reductase and hexokinase activities were released without loss of mitochondrial membrane potential indicating that part of the enzyme was released while the inner mitochondrial membrane remained intact [9].

Associations of Tb10.70.5800 with chemical compounds

• Hexokinase has a very high affinity for glucose (Km = 17 microM) and exhibits a broad pH optimum with a maximum at pH 7 [10].
• Endogenous hexokinase acts as an ATP trap favouring ATP synthesis sn-glycerol-3-phosphate and ADP [11].
• Analysis by isopycnic sedimentation in sucrose showed that both particulate enzymes co-sedimented with glycosomal-(microbody-)marker enzymes such as hexokinase [12].

Analytical, diagnostic and therapeutic context of Tb10.70.5800

• Cell fractionation showed that the enzymes involved in the early sequence of the glycolytic pathway, i.e. from hexokinase to phosphoglycerate kinase, and the enzymes NAD+-linked glycerol-3-phosphate dehydrogenase and glycerol kinase were all present in glycosomes equilibrating at a density of 1.23 g/cm3 in sucrose gradients [13].

References