Potential Anti-infective Targets in Pathogenic Yeasts: Structure and Properties of 3,4-Dihydroxy-2-butanone 4-phosphate Synthase of Candida albicans

Echt, S.; Bauer, Stefanie; Steinbacher, Stefan; Huber, Robert; Bacher, Adelbert; Fischer, Markus

doi:10.1016/j.jmb.2004.06.053

Cited by 31 publications

(57 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…15 Å . This is comparable with the RMSD values observed when different crystal structures of the same protein are superimposed on each other (Daopin et al 1994, Echt et al 2004. Consequently, the new TSH-TSHR complex consisted of the crystal structure of the TSHR LRD combined with the comparative model of the TSH in the same relative position as that observed in the crystal structure of the complex between the FSHR and FSH.…”

Section: Comparative Modellingsupporting

confidence: 78%

FSH and TSH binding to their respective receptors: similarities, differences and implication for glycoprotein hormone specificity

Miguel¹,

Sanders²,

Chirgadze³

et al. 2008

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

The crystal structures of the leucine-rich repeat domain (LRD) of the FSH receptor (FSHR) in complex with FSH and the TSH receptor (TSHR) LRD in complex with the thyroid-stimulating autoantibody (M22) provide opportunities to assess the molecular basis of the specificity of glycoprotein hormone-receptor binding. A comparative model of the TSH-TSHR complex was built using the two solved crystal structures and verified using studies on receptor affinity and activation. Analysis of the FSH-FSHR and TSH-TSHR complexes allowed identification of receptor residues that may be important in hormone-binding specificity. These residues are in leucine-rich repeats at the two ends of the FSHR and the TSHR LRD structures but not in their central repeats. Interactions in the interfaces are consistent with a higher FSH-binding affinity for the FSHR compared with the binding affinity of TSH for the TSHR. The higher binding affinity of porcine (p)TSH and bovine (b)TSH for human (h)TSHR compared with hTSH appears not to be dependent on interactions with the TSHR LRD as none of the residues that differ among hTSH, pTSH or bTSH interact with the LRD. This suggests that TSHs are likely to interact with other parts of the receptors in addition to the LRD with these non-LRD interactions being responsible for affinity differences. Analysis of interactions in the FSH-FSHR and TSH-TSHR complexes suggests that the a-chains of both hormones tend to be involved in the receptor activation process while the b-chains are more involved in defining binding specificity.

show abstract

Section: Comparative Modellingsupporting

confidence: 78%

FSH and TSH binding to their respective receptors: similarities, differences and implication for glycoprotein hormone specificity

Miguel¹,

Sanders²,

Chirgadze³

et al. 2008

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

show abstract

“…GTP cyclohydrolase is located at the C-terminal end of the fused protein, whereas 3,4-dihydroxy-2-butanone 4-phosphate synthase occupies the N-terminal part of the protein. The structure of this synthase was studied by X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy (99,220,263,264,465,466). In addition to its known function in RF synthesis, the synthase also functions somehow in the regulation of mitochondrial respiration, as the corresponding S. cerevisiae rib3 knockout mutant grew with RF in a glucose medium but not in a glycerol or ethanol medium (197).…”

Section: 4-dihydroxy-2-butanone 4-phosphate Synthasementioning

confidence: 99%

“…The active site of 3,4-dihydroxy-2-butanone 4-phosphate synthase was localized by crystallographic analysis of the enzymes from the archaeon M. jannaschii and the pathogenic yeast Candida albicans in a complex with ribulose-5-phosphate (99,465,466). A highly conserved loop comprised of several acidic amino acid residues is essential for catalysis, as shown by studies with a variety of mutant proteins (120).…”

Section: 4-dihydroxy-2-butanone 4-phosphate Synthasementioning

confidence: 99%

Genetic Control of Biosynthesis and Transport of Riboflavin and Flavin Nucleotides and Construction of Robust Biotechnological Producers

Abbas

Sibirny

2011

Microbiol Mol Biol Rev

325

272

View full text Add to dashboard Cite

SUMMARY Riboflavin [7,8-dimethyl-10-(1′- d -ribityl)isoalloxazine, vitamin B 2 ] is an obligatory component of human and animal diets, as it serves as the precursor of flavin coenzymes, flavin mononucleotide, and flavin adenine dinucleotide, which are involved in oxidative metabolism and other processes. Commercially produced riboflavin is used in agriculture, medicine, and the food industry. Riboflavin synthesis starts from GTP and ribulose-5-phosphate and proceeds through pyrimidine and pteridine intermediates. Flavin nucleotides are synthesized in two consecutive reactions from riboflavin. Some microorganisms and all animal cells are capable of riboflavin uptake, whereas many microorganisms have distinct systems for riboflavin excretion to the medium. Regulation of riboflavin synthesis in bacteria occurs by repression at the transcriptional level by flavin mononucleotide, which binds to nascent noncoding mRNA and blocks further transcription (named the riboswitch). In flavinogenic molds, riboflavin overproduction starts at the stationary phase and is accompanied by derepression of enzymes involved in riboflavin synthesis, sporulation, and mycelial lysis. In flavinogenic yeasts, transcriptional repression of riboflavin synthesis is exerted by iron ions and not by flavins. The putative transcription factor encoded by SEF1 is somehow involved in this regulation. Most commercial riboflavin is currently produced or was produced earlier by microbial synthesis using special selected strains of Bacillus subtilis , Ashbya gossypii , and Candida famata . Whereas earlier RF overproducers were isolated by classical selection, current producers of riboflavin and flavin nucleotides have been developed using modern approaches of metabolic engineering that involve overexpression of structural and regulatory genes of the RF biosynthetic pathway as well as genes involved in the overproduction of the purine precursor of riboflavin, GTP.

show abstract

“…In most of Gram-negative bacteria, DHBPS exists as monofunctional form, whereas in Gram-positive bacteria including Mycobacterium tuberculosis DHBPS co-exists with GTP cyclohydrolase II and thus is found in a bifunctional form (9,16,(27)(28)(29). Crystal structures of DHBPS from E. coli (30,31), Magnaporthe grisea (32), Methanococcus jannaschii (33), Candida albicans (34), Salmonella typhimurium (35), M. tuberculosis (28,36), and Streptococcus pneumoniae (27) have been reported. All these structures reveal that DHBPS is a homodimer where each monomer forms an ␣ ϩ ␤ fold and that its active site is located at two topologically equivalent positions at the dimeric interface of each monomer (27, 28, 30 -36).…”

Section: The Atomic Coordinates and Structure Factors (Codes 4p8j 4pmentioning

confidence: 99%

“…The DHBPS structure complexed with substrate and metal ions indicates that an acidic active site loop (Loop1) and another loop (Loop2) undergo a conformational change upon substrate and/or metal binding (32,33,35). Furthermore, these structures also reveal the amino acids involved in the proposed reaction mechanism of DHBPS (27,28,(32)(33)(34)(35)(36). Nevertheless, certain differences observed in the existing structures prevent us from predicting the molecular mechanism of DHBPS completely.…”

Section: The Atomic Coordinates and Structure Factors (Codes 4p8j 4pmentioning

confidence: 99%

Structural Basis for Competitive Inhibition of 3,4-Dihydroxy-2-butanone-4-phosphate Synthase from Vibrio cholerae

Islam

Kumar

Singh

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: 3,4-Dihydroxy-2-butanone-4-phosphate synthase (DHBPS) is essential for many pathogens and is absent in humans. Results: We have characterized DHBPS from Vibrio cholerae in the presence of substrate D-ribulose 5-phosphate (Ru5P) and inhibitor 4-phospho-D-erythronohydroxamic acid (4PEH). Conclusion: 4PEH inhibits DHBPS competitively and interacts with enzyme similarly to the substrate. Significance: 4PEH can be used as a lead molecule for designing novel antibiotics.

show abstract

Potential Anti-infective Targets in Pathogenic Yeasts: Structure and Properties of 3,4-Dihydroxy-2-butanone 4-phosphate Synthase of Candida albicans

Cited by 31 publications

References 50 publications

FSH and TSH binding to their respective receptors: similarities, differences and implication for glycoprotein hormone specificity

FSH and TSH binding to their respective receptors: similarities, differences and implication for glycoprotein hormone specificity

Genetic Control of Biosynthesis and Transport of Riboflavin and Flavin Nucleotides and Construction of Robust Biotechnological Producers

Structural Basis for Competitive Inhibition of 3,4-Dihydroxy-2-butanone-4-phosphate Synthase from Vibrio cholerae

Contact Info

Product

Resources

About