High impact information on Tb09.211.1370

• The PARP mini-exon addition region abolished transient CAT expression directed by either the gGAPDH or PARP promoters in bloodstream T. brucei implying that transplicing can be a point of stage-specific gene regulation [1].
• The gGAPDH promoter gave rise to relatively high CAT signals upon transfection into bloodstream T. brucei and relatively low signals in procyclic T. brucei, compared with levels resulting from transfection with the procyclic acidic repetitive protein (PARP) promoter [1].
• Guided by the crystal structures of human, T. brucei, and Leishmania mexicana glyceraldehyde-3-phosphate dehydrogenase, we designed adenosine analogs as tight binding inhibitors that occupy the pocket on the enzyme that accommodates the adenosyl moiety of the NAD+ cosubstrate [2].
• Although adenosine is a very poor inhibitor, IC50 approximately 50 mM, addition of substituents to the 2' position of ribose and the N6-position of adenosine led to disubstituted nucleosides with micromolar to submicromolar potency in glyceraldehyde-3-phosphate dehydrogenase assays, an improvement of 5 orders of magnitude over the lead [2].
• Gel analysis of reisolated glycosomes revealed that glyceraldehyde-3-phosphate dehydrogenase (EC 1.2.1.12) and 3-phosphoglycerate kinase (PGK) (EC 2.7.2.3) were apparently imported intact into the glycosome [3].

Biological context of Tb09.211.1370

• These proteins were found to be the glycosomal enzymes aldolase (41 kDa) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH, 36 kDa) by enzyme activity, antibody cross-reaction, and N-terminal sequencing [4].
• Synthesis and structure-activity relationships of analogs of 2'-deoxy-2'-(3-methoxybenzamido)adenosine, a selective inhibitor of trypanosomal glycosomal glyceraldehyde-3-phosphate dehydrogenase [5].
• Crystal structure of glycosomal glyceraldehyde-3-phosphate dehydrogenase from Leishmania mexicana: implications for structure-based drug design and a new position for the inorganic phosphate binding site [6].
• The length of the combined 3' untranslated region and poly(A) tail does not control rates of glyceraldehyde-3-phosphate dehydrogenase mRNA translation in three species of parasitic protists [7].
• This last specific metabolic arrangement and the restriction of all but the terminal steps of glycolysis to the glycosome may be the observations required to explain the presence of distinct cytosolic and glycosomal isoenzymes of glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase [8].

Anatomical context of Tb09.211.1370

• By contrast, in erythrocytes more than 95% deficiencies of PGK, GAPDH, or ALD did not cause any clinical symptoms (Schuster, R. and Holzhütter, H.-G. (1995) Eur. J. Biochem. 229, 403-418) [9].

Associations of Tb09.211.1370 with chemical compounds

• This information was used for the design of two series of glyceraldehyde 3-phosphate analogues with similar reactive groups that could function as potential irreversible inhibitors of glyceraldehyde-3-phosphate dehydrogenase [10].

Analytical, diagnostic and therapeutic context of Tb09.211.1370

• Regions 5' of the glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) gene from Trypanosoma brucei were tested for their ability to promote chloramphenicol acetyl-transferase (CAT) expression on reintroduction by electroporation into the parasite [1].

References