Structural and Mutational Analysis of Trypanosoma brucei Prostaglandin H2 Reductase Provides Insight into the Catalytic Mechanism of Aldo-ketoreductases

Kilunga, Kubata Bruno; Inoue, Tsuyoshi; Okano, Yasuhiro; Kabututu, Zakayi; Martin, Samuel K.; Lazarus, Michael; Duszenko, Michael; Sumii, Y.; Kusakari, Yukiko; Matsumura, Hideki; Sugiyama, Shigeru; Inaka, Kouji; Inui, Takashi; Urade, Yoshihiro

doi:10.1074/jbc.m413884200

Cited by 22 publications

(30 citation statements)

References 50 publications

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“…Furthermore, a catalytic role of His-110 could not be entirely excluded. Quantum mechanical calculations of the energetics of reaction pathway (Lee et al, 1998) support a primary role of His-110 in AKR1B catalysis and in recent analysis of AKR5A2 catalysis, Kilunga et al (Kilunga et al, 2005), found that of the 4 residues of the catalytic tetrad, only His-110 and Lys-77 are important for the reduction of PGH 2 to PGF 2α , and that active site tyrosine and aspartate were not required. Active site tyrosine was, however, required for the reduction of the non-physiological substrate 9,10-phenanthroquinone.…”

Section: B) Catalytic Properties Of Akrsmentioning

confidence: 99%

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

Barski

Tipparaju

Bhatnagar

2008

Drug Metabolism Reviews

434

340

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The Aldo-Keto Reductase (AKR) superfamily comprises of several enzymes that catalyze redox transformations involved in biosynthesis, intermediary metabolism and detoxification. Substrates of the family include glucose, steroids, glycosylation end products, lipid peroxidation products, and environmental pollutants. These proteins adopt a (β/α) 8 barrel structural motif interrupted by a number of extraneous loops and helixes that vary between proteins and bring structural identity to individual families. The human AKR family differs from the rodent families. Due to their broad substrate specificity, AKRs play an important role in the Phase II detoxification of a large number of pharmaceuticals, drugs, and xenobiotics.

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Section: B) Catalytic Properties Of Akrsmentioning

confidence: 99%

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

Barski

Tipparaju

Bhatnagar

2008

Drug Metabolism Reviews

434

340

View full text Add to dashboard Cite

show abstract

“…It is hypothesized that ablation of a signal or induction of an inappropriate signal will be lethal to these cells. From past experiments it is clear that trypanosomes have the potential to propagate signals involving Ca 2ϩ , cyclic nucleotides, eicosenoic acid, and phosphoryl transfer (1)(2)(3)(4). However, in stark contrast with mammalian cells, where complex interacting signal networks have been described, a simple signal pathway has yet to be identified in Trypanosoma brucei.…”

mentioning

confidence: 99%

The RACK1 Homologue from Trypanosoma brucei Is Required for the Onset and Progression of Cytokinesis

Rothberg

Burdette

Pfannstiel

et al. 2006

Journal of Biological Chemistry

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The receptor for activated C kinase 1 (RACK1) is a conserved scaffold protein that helps regulate a range of cell activities including cell growth, shape, and protein translation. We report that a homologue of RACK1 is required for cytokinesis in pathogenic Trypanosoma brucei. The protein, referred to as TRACK, is comprised of WD repeat elements and can complement cpc2 null mutants of Schizosaccharomyces pombe. TRACK is expressed throughout the trypanosome life cycle and is distributed predominantly in a perinuclear region and the cytoplasm but not along the endoplasmic reticulum, mitochondrion, or cleavage furrow of dividing cells. When tetracycline-inducible RNA interference (RNAi) is used to deplete the cellular content of TRACK, the cells remain metabolically active, but growth is inhibited. In bloodstream forms, growth arrest is due to a delay in the onset of cytokinesis. By contrast, procyclic forms are able to initiate cytokinesis in the absence of TRACK but arrest midway through cell cleavage. The RNAi cells undergo multiple rounds of partial cytokinesis and accumulate nuclei and cytoplasmic extensions with attached flagella. The TRACK RNAi construct is also inducible within infected mice. Under these conditions parasites are eliminated from peripheral blood within 3 days post-infection. Taken as a whole, these data indicate that trypanosomes utilize a RACK1 homologue to regulate the final stages of mitosis. Moreover, disrupting the interaction between TRACK and its partners might be targeted in the design of novel therapies.African trypanosomes are protozoan parasites that produce lethal infections in humans and livestock throughout sub-Saharan Africa. Trypanosomes have a complex life cycle that involves changes in morphology, biochemistry, and gene expression as the cells pass through a variety of different environments. Signal cascades are predicted to mediate complex life cycle events and initiate rapid changes in cell behavior. It is hypothesized that ablation of a signal or induction of an inappropriate signal will be lethal to these cells. From past experiments it is clear that trypanosomes have the potential to propagate signals involving Ca 2ϩ , cyclic nucleotides, eicosenoic acid, and phosphoryl transfer (1-4). However, in stark contrast with mammalian cells, where complex interacting signal networks have been described, a simple signal pathway has yet to be identified in Trypanosoma brucei. To remedy this situation we began to study a putative signal anchor protein and the pathways it regulates.In general, anchor proteins help provide spatial organization to the signal process by allowing the formation of multimeric complexes at the appropriate location in the cell (5). Additionally, association with different anchors allows some signal kinases to participate in and distinguish between multiple pathways. The receptor for activated C kinase-1 (RACK1 2 is a WD repeat protein that forms ternary complexes with a range of signal proteins (for review, see Ref. 6). Target proteins interact with RACK1...

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“…However in T. brucei three ALRs have been reported. One of the aldo-keto reductase from T. brucei has a known three-dimensional structure (Kilunga et al, 2005). A sequence analysis was performed with the ALR sequences of Leishmania, T. brucei sequence with known structure along with the experimentally characterized aldose reductase sequences from human, yeast and other known aldose reductase sequences.…”

Section: Relationship Of Ldalr To Other Members Of the Aldose-keto Rementioning

confidence: 99%

“…The modeling has been based on the available (2.1 Å) crystal structure of T. brucei brucei Prostaglandin-F-synthase (TbPGFS) structure (Kilunga et al, 2005) which is identified as the closest homologue of LdALR of known 3-D structure. The best sequence identity between T. brucei homologue and LdALR is 61%.…”

Section: Comparative Modeling Of L Donovani Aldose Reductasementioning

confidence: 99%

A glutathione-specific aldose reductase of Leishmania donovani and its potential implications for methylglyoxal detoxification pathway

Rath

Gowri

Chauhan

et al. 2009

Gene

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Structural and Mutational Analysis of Trypanosoma brucei Prostaglandin H2 Reductase Provides Insight into the Catalytic Mechanism of Aldo-ketoreductases

Cited by 22 publications

References 50 publications

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

The RACK1 Homologue from Trypanosoma brucei Is Required for the Onset and Progression of Cytokinesis

A glutathione-specific aldose reductase of Leishmania donovani and its potential implications for methylglyoxal detoxification pathway

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