Summary: 6,7-dimethyl-8-ribityllumazine synthase
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This is the Wikipedia entry entitled "Riboflavin synthase". More...
Riboflavin synthase Edit Wikipedia article
| Riboflavin synthase | |||||||||
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| Identifiers | |||||||||
| EC number | 2.5.1.9 | ||||||||
| CAS number | 9075-82-5 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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| 6,7-dimethyl-8-ribityllumazine synthase | |||||||||||
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| Identifiers | |||||||||||
| Symbol | DMRL_synthase | ||||||||||
| Pfam | PF00885 | ||||||||||
| InterPro | IPR002180 | ||||||||||
| SCOPe | 1rvv / SUPFAM | ||||||||||
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Riboflavin synthase is an enzyme that catalyzes the final reaction of riboflavin biosynthesis:
(2) 6,7-dimethyl-8-ribityllumazine → riboflavin + 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione
Contents
Structure
The Riboflavin synthase monomer is 23kDa. Each monomer contains two beta-barrels and one α-helix at the C-terminus (residues 186-206.) The monomer folds into pseudo two-fold symmetry, predicted by sequence similarity between the N-terminus barrels (residues 4-86) and the C-terminus barrel (residues 101-184).[1] The enzyme from different species adopts different quaternary structures, from monomeric to 60 subunits[3]
Active site
Two 6,7-dimethyl-8-ribityllumazine (Lumazine synthase) molecules are hydrogen bound to each monomer as the two domains are topologically similar.[4] The active site is located in the interface of the substrates between monomer pairs and modeled structures of the active site dimer have been created.[2] Only one of the active sites of the enzyme catalyze riboflavin formation at a time as the other two sites face outward and are exposed to solvent.[1] The amino acid residues involved in hydrogen bonding to the ligand are pictured, participating residues may include Thr148, Met160, Ile162, Thr165, Val6, Tyr164, Ser146, and Gly96 at the C-terminal domain and Ser41, Thr50, Gly 62, Ala64, Ser64, Val103, Cys48, His102 at the N-terminal domain.[5]
Hydrogen bonding between substrate and enzyme at the C-terminal domain.[2]
Hydrogen bonding between substrate and enzyme at the N-terminal domain.[2]
Mechanism
No cofactors are needed for catalysis. Additionally, the formation of riboflavin from 6,7-dimethyl-8-ribityllumazine can occur in boiling aqueous solution in the absence riboflavin synthase.[6]
At the interface of the substrate between monomer pairs, the enzyme holds the two 6,7-dimethyl-8-ribityllumazine molecules in position via hydrogen bonding to catalyze the dismutation reaction.[6] Additionally, acid/base catalysis by the amino acid residues has been suggested. Specific residues may include the His102/Thr148 dyad as a base for deprotonation of the C7a methyl group. Of the dyad, His102 is from the N-barrel and Thr148 is from the C-barrel, highlighting the importance of the proximity of the two subunits of the enzyme in the early stages of the reaction.[7] It has also been suggested that the identity of the nucleophile is one of the following conserved residues: Ser146, Ser41, Cys48, or Thr148, or water in the uncatalyzed reaction.[1] In studies on the role of Cys48 as a possible nucleophile, it has not been determined if nucleophilic displacement occurs via an SN1 or SN2 reaction.[7]
Drug Production
Scientists have hypothesized that enzymes involved in the riboflavin biosynthesis pathway, including riboflavin synthase, can be used to develop antibacterial drugs in order to treat infections caused by Gram-negative bacteria and yeasts. This hypothesis is based on the inability of Gram-negative bacteria, such as E. coli and S. typhimurium, to uptake riboflavin from the external environment.[5][8] As Gram-negative bacteria need to produce their own riboflavin, inhibiting riboflavin synthase or other enzymes involved in the pathway may be useful tools in developing antibacterial drugs.
The most potent riboflavin synthase inhibitor is 9-D-ribityl-1,3,7-trihydropurine-2,6,8-trione, with Ki value of 0.61 μM. 9-D-ribityl-1,3,7-trihydropurine-2,6,8-trione is thought to work through competitive inhibition with 6,7-dimethyl-8-ribityllumazine.[8]
See also
References
- ^ a b c d PDB: 1i8d; Liao DI, Wawrzak Z, Calabrese JC, Viitanen PV, Jordan DB (May 2001). "Crystal structure of riboflavin synthase". Structure. 9 (5): 399–408. doi:10.1016/S0969-2126(01)00600-1. PMID 11377200.
- ^ a b c d PDB: 1kzl; Gerhardt S, Schott AK, Kairies N, Cushman M, Illarionov B, Eisenreich W, Bacher A, Huber R, Steinbacher S, Fischer M (October 2002). "Studies on the reaction mechanism of riboflavin synthase: X-ray crystal structure of a complex with 6-carboxyethyl-7-oxo-8-ribityllumazine". Structure. 10 (10): 1371–81. doi:10.1016/S0969-2126(02)00864-X. PMID 12377123.
- ^ http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/enzyme/?ec=2.5.1.9&tab=assemblies
- ^ Fischer M, Schott AK, Kemter K, Feicht R, Richter G, Illarionov B, Eisenreich W, Gerhardt S, Cushman M, Steinbacher S, Huber R, Bacher A (December 2003). "Riboflavin synthase of Schizosaccharomyces pombe. Protein dynamics revealed by 19F NMR protein perturbation experiments". BMC Biochem. 4: 18. doi:10.1186/1471-2091-4-18. PMC 337094. PMID 14690539.
- ^ a b Fischer M, Bacher A (June 2008). "Biosynthesis of vitamin B2: Structure and mechanism of riboflavin synthase". Arch. Biochem. Biophys. 474 (2): 252–65. doi:10.1016/j.abb.2008.02.008. PMID 18298940.
- ^ a b Bacher A, Eberhardt S, Fischer M, Kis K, Richter G (2000). "Biosynthesis of vitamin b2 (riboflavin)". Annu. Rev. Nutr. 20: 153–67. doi:10.1146/annurev.nutr.20.1.153. PMID 10940330.
- ^ a b Zheng YJ, Jordan DB, Liao DI (August 2003). "Examination of a reaction intermediate in the active site of riboflavin synthase". Bioorg. Chem. 31 (4): 278–87. doi:10.1016/S0045-2068(03)00029-4. PMID 12877878.
- ^ a b Cushman M, Yang D, Kis K, Bacher A (December 2001). "Design, synthesis, and evaluation of 9-D-ribityl-1,3,7-trihydro-2,6,8-purinetrione, a potent inhibitor of riboflavin synthase and lumazine synthase". J. Org. Chem. 66 (25): 8320–7. doi:10.1021/jo010706r. PMID 11735509.
External links
- Riboflavin+synthase at the US National Library of Medicine Medical Subject Headings (MeSH)
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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
6,7-dimethyl-8-ribityllumazine synthase Provide feedback
This family includes the beta chain of 6,7-dimethyl-8- ribityllumazine synthase EC:2.5.1.9, an enzyme involved in riboflavin biosynthesis. The family also includes a subfamily of distant archaebacterial proteins that may also have the same function for example O28856. The family contains a number of different subsets including a family of proteins comprising archaeal lumazine and riboflavin synthases, type I lumazine synthases, and the eubacterial type II lumazine synthases [1]. It has been established that lumazine synthase catalyses the penultimate step in the biosynthesis of riboflavin in plants and microorganisms. The type I lumazine synthases area active in pentameric or icosahedral quaternary assemblies, whereas the type II are decameric [2]. Brucella, a bacterial genus that causes brucellosis, and other Rhizobiales have an atypical riboflavin metabolic pathway. Brucella spp code for both a type-I and a type-II lumazine synthase, and it has been shown that at least one of these two has to be present in order for Brucella to be viable, showing that in the case of Brucella flavin metabolism is implicated in bacterial virulence [3].
Literature references
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Zylberman V, Klinke S, Haase I, Bacher A, Fischer M, Goldbaum FA;, J Bacteriol. 2006;188:6135-6142.: Evolution of vitamin B2 biosynthesis: 6,7-dimethyl-8-ribityllumazine synthases of Brucella. PUBMED:16923880 EPMC:16923880
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Klinke S, Zylberman V, Bonomi HR, Haase I, Guimaraes BG, Braden BC, Bacher A, Fischer M, Goldbaum FA;, J Mol Biol. 2007;373:664-680.: Structural and kinetic properties of lumazine synthase isoenzymes in the order Rhizobiales. PUBMED:17854827 EPMC:17854827
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Bonomi HR, Marchesini MI, Klinke S, Ugalde JE, Zylberman V, Ugalde RA, Comerci DJ, Goldbaum FA;, PLoS One. 2010;5:e9435.: An atypical riboflavin pathway is essential for Brucella abortus virulence. PUBMED:20195542 EPMC:20195542
External database links
| HOMSTRAD: | DMRL_synthase |
| SCOP: | 1rvv |
This tab holds annotation information from the InterPro database.
InterPro entry IPR002180
6,7-dimethyl-8-ribityllumazine synthase (lumazine synthase, LS), catalyzes the formation of 6,7-dimethyl-8-ribityllumazine by condensation of 5-amino-6-(D-ribitylamino)uracil with 3,4-dihydroxy-2-butanone 4-phosphate, the penultimate step in the biosynthesis of riboflavin.
The biosynthesis of one riboflavin molecule requires one molecule of GTP and two molecules of ribulose 5-phosphate as substrates. The final step in the biosynthesis of the vitamin involves the dismutation of 6,7-dimethyl-8-ribityllumazine catalyzed by riboflavin synthase (RS). The second product, 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione, is recycled in the biosynthetic pathway by 6,7-dimethyl-8-ribityllumazine synthase [ PUBMED:18298940 ]. N-[2,4-dioxo-6-d-ribitylamino-1,2,3,4-tetrahydropyrimidin-5-yl]oxalamic acid derivatives inhibit riboflavin synthase [ PUBMED:18331058 ].
This family includes both lumazine synthase and riboflavin synthase. Both share sequence similarity, they appear to have diverged early in the evolution of archaea from a common ancestor.
Gene Ontology
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
| Cellular component | riboflavin synthase complex (GO:0009349) |
| Biological process | riboflavin biosynthetic process (GO:0009231) |
Domain organisation
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Alignments
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RP35 (4187) |
RP55 (8726) |
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| Seed (603) |
Full (8814) |
Representative proteomes | UniProt (38132) |
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| RP15 (1198) |
RP35 (4187) |
RP55 (8726) |
RP75 (15044) |
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| Raw Stockholm | |||||||
| Gzipped | |||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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Curation and family details
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Curation
| Seed source: | Pfam-B_1503 (release 3.0) |
| Previous IDs: | none |
| Type: | Domain |
| Sequence Ontology: | SO:0000417 |
| Author: |
Bateman A 
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| Number in seed: | 603 |
| Number in full: | 8814 |
| Average length of the domain: | 140.60 aa |
| Average identity of full alignment: | 38 % |
| Average coverage of the sequence by the domain: | 82.82 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 141 | ||||||||||||
| Family (HMM) version: | 21 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Structures
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the DMRL_synthase domain has been found. There are 1080 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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