Crystal structure of 7,8-dihydroneopterin triphosphate epimerase

Ploom, Tarmo; Haussmann, Christoph; Hof, Peter; Steinbacher, Stefan; Bacher, Adelbert; Richardson, Jeffrey Ralph James; Huber, Robert

doi:10.1016/s0969-2126(99)80067-7

Cited by 26 publications

(24 citation statements)

References 22 publications

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“…T-fold enzymes bind planar purine and pterinlike substrates but catalyze disparate reactions (43), and although they characteristically exhibit low sequence homology, their tertiary structural homology is very high. Using the N. gonorrhoeae sequence as a bait, the N-terminal half of COG1469 is most similar in predicted tertiary structure to 7,8-dihydroneopterin triphosphate epimerase (Protein Data Bank code 1B9L (44), PSSM E value 0.39), whereas the C-terminal half is similar to 7,8-dihydroneopterin aldolase (DHNA; Protein Data Bank code 1NBU (45), PSSM E value 0.3) (Fig. 5A).…”

Section: Discussionmentioning

confidence: 99%

Discovery of a New Prokaryotic Type I GTP Cyclohydrolase Family

Yacoubi

Bonnett

Anderson

et al. 2006

Journal of Biological Chemistry

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GTP cyclohydrolase I (GCYH-I) is the first enzyme of the de novo tetrahydrofolate biosynthetic pathway present in bacteria, fungi, and plants, and encoded in Escherichia coli by the folE gene. It is also the first enzyme of the biopterin (BH4) pathway in Homo sapiens, where it is encoded by a homologous folE gene. A homology-based search of GCYH-I orthologs in all sequenced bacteria revealed a group of microbes, including several clinically important pathogens, that encoded all of the enzymes of the tetrahydrofolate biosynthesis pathway but GCYH-I, suggesting that an alternate family was present in these organisms. A prediction based on phylogenetic occurrence and physical clustering identified the COG1469 family as a potential candidate for this missing enzyme family. The GCYH-I activity of COG1469 family proteins from a variety of sources (Thermotoga maritima, Bacillus subtilis, Acinetobacter baylyi, and Neisseria gonorrhoeae) was experimentally verified in vivo and/or in vitro. Although there is no detectable sequence homology with the canonical GCYH-I, protein fold recognition based on sequence profiles, secondary structure, and solvation potential information suggests that, like GCYH-I proteins, COG1469 proteins are members of the tunnel-fold (T-fold) structural superfamily. This new GCYH-I family is found in ϳ20% of sequenced bacteria and is prevalent in Archaea, but the family is to this date absent in Eukarya.

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Section: Discussionmentioning

confidence: 99%

Discovery of a New Prokaryotic Type I GTP Cyclohydrolase Family

Yacoubi

Bonnett

Anderson

et al. 2006

Journal of Biological Chemistry

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“…FolX forms an octameric ring-like structure where the entire protein appears to be required for proper folding (PDB accession no. 1B9L) (44). However, we cannot conclude that subdomains are not suffi-cient for the oligomerization of most proteins where the IST covers the entire ORF, as we may have simply failed to sample the appropriate fragments.…”

Section: Discussionmentioning

confidence: 93%

Identification and Mapping of Self-Assembling Protein Domains Encoded by theEscherichia coliK-12 Genome by Use of λ Repressor Fusions

et al. 2004

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Self-assembling proteins and protein fragments encoded by the Escherichia coli genome were identified from E. coli K-12 strain MG1655. Libraries of random DNA fragments cloned into a series of repressor fusion vectors were subjected to selection for immunity to infection by phage . Survivors were identified by sequencing the ends of the inserts, and the fused protein sequence was inferred from the known genomic sequence. Four hundred sixty-three nonredundant open reading frame-encoded interacting sequence tags (ISTs) were recovered from sequencing 2,089 candidates. These ISTs, which range from 16 to 794 amino acids in length, were clustered into families of overlapping fragments, identifying potential homotypic interactions encoded by 232 E. coli genes. Repressor fusions identified ISTs from genes in every protein-based functional category, but membrane proteins were underrepresented. The IST-containing genes were enriched for regulatory proteins and for proteins that form higher-order oligomers. Forty-eight (20.7%) homotypic proteins identified by ISTs are predicted to contain coiled coils. Although most of the IST-containing genes are identifiably related to proteins in other bacterial genomes, more than half of the ISTs do not have identifiable homologs in the Protein Data Bank, suggesting that they may include many novel structures. The data are available online at http://oligomers.tamu.edu/.For many proteins, quaternary structure is intimately coupled to function and stability. This coupling allows the regulation of many cellular processes to be controlled through specific assembly or disassembly of protein complexes as well as by conformational changes that alter how subunits contact one another.Proteins use a wide variety of quaternary structures to assemble multisubunit complexes. Genome-wide identification of protein interactions by use of genetic (21,36,46,57,58) or biochemical (15,19,41) screens has provided a wealth of insight into the diversity of structures used for self-assembly. In the annotation of predicted open reading frames (ORFs), assembly interactions are an important feature that provides insights into structure and function. In addition, the involvement of a gene product in a multimeric complex suggests strategies for the generation of assembly-based inhibitors for functional studies (18). The possibility that protein interactions represent a large and largely underexploited target for drug discovery has also been discussed (6,55) The study of the protein interactome has focused on heterotypic interactions, as these can provide links between proteins of unknown function and proteins of known function. However, homotypic interactions, which are found in both homomultimeric proteins and as subcomplexes of heteromultimeric proteins, may be the most common way to form protein complexes in nature (31). Although by definition self-interaction does not link a protein's function to that of another protein, homotypic interactions are important in the study of protein structure, function, and evol...

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“…The chemistry performed by these enzymes is diverse and the reaction mechanism utilized by each enzyme of the superfamily is significantly different. In terms of structure, each of these proteins contains a Tunneling-fold domain but the number of subunits required to form a functional enzyme varies 47 .…”

Section: Discussionmentioning

confidence: 99%

“…The biological role of this enzyme and reaction product remains unclarified. 33,47 Urate oxidase (UOX) is a bimodular T-fold enzyme responsible for the conversion of uric acid to allantoin ( Figure 3F). 48 It catalyzes the oxidative ring opening of the purine ring in the purine degradation pathway.…”

Section: The T-fold Superfamilymentioning

confidence: 99%

“…The functional T-fold enzymes differ in size and number of monomers that constitute the functional protein. GCYH-1A is a homodecamer (Dimer of pentamers, Figure 5A), GCYH-1B is a homotetramer, DNHA ( Figure 5B) and dihydroneopterin epimerase ( Figure 5C) are homooctamers (dimers of tetramers), PTPS is a homohexamer (dimer of trimers, Figure 5D), and UOX is a homotetramer ( Figure 5E) 31,35,47,50 . …”

Section: The T-fold Superfamilymentioning

confidence: 99%

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QueF and QueF-like: Diverse Chemistries in a Common Fold

Ramos¹

2000

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The tunneling fold (T-Fold) superfamily is a small superfamily of enzymes found in organisms encompassing all kingdoms of life. Seven members have been identified thus far. Despite sharing a common three-dimensional structure these enzymes perform very diverse chemistries.QueF is a bacterial NADPH-dependent oxidoreductase that catalyzes the reduction of the nitrile group of 7-cyano-7-deazaguanine (preQ0) to a primary amine (preQ1) in the queuosine biosynthetic pathway. Previous work on this enzyme has revealed the mechanism of reaction but the cofactor binding Based on bond angles and energies, the disulfide bond between Cys55 and Cys99 was characterized as non-structural. Enzyme oxidation assays were consistent with the bond serving to protect QueF against irreversible oxidation of ii Cys55, which would render the enzyme inactive. This is the only known example of a stress protective mechanism in the Tunneling-fold superfamily.QueF-like is an amidinotransferase found in some species of Crenarchaeota and involved in the biosynthesis of archaeosine-tRNA. The work presented here is focused on the preliminary characterization of this enzyme, including the elucidation of the natural substrate as well as the source of ammonia. The structure of the enzyme was solved and is also discussed.Substrate analysis for QueF-like indicated this enzyme is capable of binding both preQ0 and preQ0-tRNA and reacting to form a thioimide intermediate analogous to QueF but only the latter serves as a substrate for the reaction. This makes QueF-like the first example of a nucleic acid binding enzyme in the Tunnelingfold superfamily. Ammonia, glutamine and asparagine were tested as nitrogen sources and unlike most known amidotransferases, QueF-like can only use free ammonia to produce the archaeosine-tRNA product. The crystal structure of P.calidifontis QueF-like indicates the functional enzyme is a dimer of pentamers pinned together by a large number of salt bridges. The structure presents a high degree of similarity to that of QueF albeit the higher twist of the QueF-like pentamers with respect to QueF results in a more compact structure.iii DedicationThis dissertation is dedicated to my husband Aaron, who's belief in my strength and capabilities has always surpassed my own.

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Crystal structure of 7,8-dihydroneopterin triphosphate epimerase

Cited by 26 publications

References 22 publications

Discovery of a New Prokaryotic Type I GTP Cyclohydrolase Family

Discovery of a New Prokaryotic Type I GTP Cyclohydrolase Family

Identification and Mapping of Self-Assembling Protein Domains Encoded by theEscherichia coliK-12 Genome by Use of λ Repressor Fusions

QueF and QueF-like: Diverse Chemistries in a Common Fold

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