The Three-dimensional Structure of the Bifunctional 6-Hydroxymethyl-7,8-Dihydropterin Pyrophosphokinase/Dihydropteroate Synthase of Saccharomyces cerevisiae

Lawrence, Michael C.; Iliades, Peter; Fernley, Ross T.; Berglez, Janette; Pilling, Patricia A.; Macreadie, Ian

doi:10.1016/j.jmb.2005.03.021

Cited by 54 publications

(60 citation statements)

References 73 publications

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“…In Burkholderia fungorum LB400, a protein containing a COG5285 domain is involved in biosynthesis of mitomycin antibiotics and the polyketide, fumonisin. Dihydropteroate synthase (Afu3g07630) has been associated with drug resistance in Saccharomyces cerevisiae and has been shown to be derived from a polycistronic gene also responsible for the production of two other functional proteins [16]. Catalase 1 (Afu3g02270) involved in oxidative stress and identified here as three separate protein spots has been implicated in A. fumigatus pathogenicity [17].…”

Section: Aspergillus Fumigatus Proteome Analysismentioning

confidence: 89%

Analysis of major intracellular proteins of Aspergillus fumigatus by MALDI mass spectrometry: Identification and characterisation of an elongation factor 1B protein with glutathione transferase activity

Carberry

Neville

Kavanagh

et al. 2006

Biochemical and Biophysical Research Communications

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Aspergillus fumigatus is a recognised human pathogen, especially in immunocompromised individuals. The availability of the annotated A. fumigatus genome sequence will significantly accelerate our understanding of this organism. However, limited information is available with respect to the A. fumigatus proteome. Here, both a direct proteomic approach (2D-PAGE and MALDI-MS) and a sub-proteomic strategy involving initial glutathione affinity chromatography have been deployed to identify 54 proteins from A. fumigatus primarily involved in energy metabolism and protein biosynthesis. Furthermore, two novel eukaryotic elongation factor proteins (eEF1Bc), termed ElfA and B have been identified and phylogenetically confirmed to belong to the eEF1Bc class of GST-like proteins. One of these proteins (ElfA) has been purified to homogeneity, identified as a monomeric enzyme (molecular mass = 20 kDa; pI = 5.9 and 6.5), and found to exhibit glutathione transferase activity specific activities (mean ± standard deviation, n = 3) of 3.13 ± 0.27 and 3.43 ± 1.0 lmol/min/mg, using CDNB and ethacrynic acid, respectively. Overall, these data highlight the importance of new approaches to dissect the proteome of, and elucidate novel functions within, A. fumigatus.

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Section: Aspergillus Fumigatus Proteome Analysismentioning

confidence: 89%

Analysis of major intracellular proteins of Aspergillus fumigatus by MALDI mass spectrometry: Identification and characterisation of an elongation factor 1B protein with glutathione transferase activity

Carberry

Neville

Kavanagh

et al. 2006

Biochemical and Biophysical Research Communications

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“…The 3D structure of selected original Saccharomyces cerevisiae gene templates (Lawrence et al, 2005) were used as starting point for homology modeling (Fig. 5A).…”

Section: Tertiary Structure Of Folate Proteinmentioning

confidence: 99%

A Novel Hydroxymethyldihydropterin Pyrophosphokinase-dihydropteroate Synthase (HPPK-DHPS) Gene from a Nutraceutical Plant Seabuckthorn, Involved in Folate Pathway is Predominantly Expressed in Fruit Tissue

Arif¹,

Khan²,

Gardezi³

et al. 2016

IJAB

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“…Over twenty HPPK structures have been deposited from five different species to date e.g. E. coli [86], H. influenza [87], S. pneumoniae [79], and S. cerevisiae [88], Y. pestis [89]). Those from S. cerevisiae and S. pneumoniae have been solved as bifunctional enzymes with either DHPS or DHNA respectively.…”

Section: Pyrophosphoryl Transfer -Hppkmentioning

confidence: 99%

Folate Biosynthesis - Reappraisal of Old and Novel Targets in the Search for New Antimicrobials

Swarbrick

Iliades

Simpson

et al. 2008

TOEIJ

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Folate biosynthesis remains a key target for antimicrobial therapy. Folate is an essential vitamin (vitamin B9) that is required for many one-carbon transfer reactions and is a critical precursor for the biosynthesis of purines, pyrimidines, and amino acids. Unlike higher eukaryotes that scavenge preformed folates, prokaryotic and lower eukaryotic microorganisms are dependent on several enzymes for the de novo biosynthesis of folate. One of these enzymes, dihydropteroate synthase (DHPS), is the target of the first chemically-synthesized antimicrobial agents, the sulfadrugs, which date back to the 1940s. Others are essential enzymes that remain to be explored as drug targets. Resistance to the sulfadrugs rapidly emerges due to the ability of the microbe to alter its susceptibility to the drug by various means. Recently a number of new structures of the enzymes in the pathway has become available. We review the recent literature relating to these targets (the enzymes: GTP cyclohydrolase (GTP-CH); 7,8-dihydroneopterin aldolase (DHNA), 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), dihydropteroate synthase (DHPS), dihydrofolate synthase (DHFS)), their mode of action and how current drugs may modulate this on a structural level. Furthermore, these data advance our understanding of the emergence of drug resistance and may aid efforts and play a major role in the design of new, more effective compounds as antimicrobial agents. To this end we also review the recent literature in the development of inhibitors of these enzymes. Future progress in this key area has the potential to benefit the war against devastating organisms such as drug-resistant Staphylococcus aureus and Plasmodium falciparum.

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The Three-dimensional Structure of the Bifunctional 6-Hydroxymethyl-7,8-Dihydropterin Pyrophosphokinase/Dihydropteroate Synthase of Saccharomyces cerevisiae

Cited by 54 publications

References 73 publications

Analysis of major intracellular proteins of Aspergillus fumigatus by MALDI mass spectrometry: Identification and characterisation of an elongation factor 1B protein with glutathione transferase activity

Analysis of major intracellular proteins of Aspergillus fumigatus by MALDI mass spectrometry: Identification and characterisation of an elongation factor 1B protein with glutathione transferase activity

A Novel Hydroxymethyldihydropterin Pyrophosphokinase-dihydropteroate Synthase (HPPK-DHPS) Gene from a Nutraceutical Plant Seabuckthorn, Involved in Folate Pathway is Predominantly Expressed in Fruit Tissue

Folate Biosynthesis - Reappraisal of Old and Novel Targets in the Search for New Antimicrobials

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