If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: riboflavin, FMN and FAD biosynthesis, vitamin B2 biosynthesis
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Vitamins Biosynthesis → Flavin Biosynthesis|
Riboflavin is the precursor for the essential flavin cofactors FMN and FAD, which are used in a wide variety of redox reactions. Riboflavin is also known as vitamin B2, because it is an essential nutrient and can not be synthesized by mammals.
The biosynthesis of one riboflavin molecule requires one molecule of GTP and two molecules of D-ribulose 5-phosphate as substrates. The imidazole ring of GTP is hydrolytically opened, yielding a 4, 5-diaminopyrimidine which is converted to 5-amino-6-(D-ribitylamino)uracil by a sequence of deamination, side chain reduction and dephosphorylation. Condensation of 5-amino-6-(D-ribitylamino)uracil with 1-deoxy-L-glycero-tetrulose 4-phosphate obtained from D-ribulose 5-phosphate results in the formation of 6,7-dimethyl-8-(1-D-ribityl)lumazine. Dismutation of the lumazine derivative yields riboflavin and 5-amino-6-(D-ribitylamino)uracil, which is recycled in the pathway [Bacher00].
The riboflavin biosynthesis pathway and its enzymes are well understood, although the enzymes catalyzing the dephosphorylation of 5-amino-6-(5-phospho-D-ribitylamino)uracil has been identified only recently [Haase13].
Several bifunctional enzymes are involved in this pathway in Escherichia coli and Bacillus subtilis. One bifunctional enzyme catalyzes the two steps required for converting 2,5-diamino-6-(5-phospho-D-ribosylamino)pyrimidin-4(3H)-one to 5-amino-6-(5-phospho-D-ribitylamino)uracil. Another such enzyme catalyzes the last two steps of the pathway, riboflavin kinase and FMN adenylyltransferase.
In addition, in both Escherichia coli and Bacillus subtilis riboflavin synthase/6,7-dimethyl-8-ribityllumazine synthase complex is a bifunctional enzyme complex that catalyzes the two steps leading from 5-amino-6-(D-ribitylamino)uracil and 1-deoxy-L-glycero-tetrulose 4-phosphate to riboflavin via 6,7-dimethyl-8-(1-D-ribityl)lumazine. This complex consists of a core of three α subunits and 60 β subunits arranged in an icosahedral capsid around the α trimer in the central core [Ritsert95].
Different variations of the pathway are found in the different kingdoms of life. The enzymes catalyzing the fungal pathway are similar to the bacterial/plant ones, but there is a difference in the order in which they act. Two enzymatic steps are required to convert 2,5-diamino-6-(5-phospho-D-ribosylamino)pyrimidin-4(3H)-one to 5-amino-6-(5-phospho-D-ribitylamino)uracil - a demaination and a reduction. In bacteria and plants, the deaminase acts first, followed by the reductase (although both steps are catalyzed by a single bifunctional enzyme in some organisms) [Fischer04a], while in fungi the reductase acts first, followed by the deaminase (see flavin biosynthesis III (fungi)). The archaeal pathway also differs in several steps (see flavin biosynthesis II (archaea)).
Fischer04a: Fischer M, Romisch W, Saller S, Illarionov B, Richter G, Rohdich F, Eisenreich W, Bacher A (2004). "Evolution of vitamin B2 biosynthesis: structural and functional similarity between pyrimidine deaminases of eubacterial and plant origin." J Biol Chem 279(35);36299-308. PMID: 15208317
Haase13: Haase I, Sarge S, Illarionov B, Laudert D, Hohmann HP, Bacher A, Fischer M (2013). "Enzymes from the haloacid dehalogenase (HAD) superfamily catalyse the elusive dephosphorylation step of riboflavin biosynthesis." Chembiochem 14(17);2272-5. PMID: 24123841
Ritsert95: Ritsert K, Huber R, Turk D, Ladenstein R, Schmidt-Base K, Bacher A (1995). "Studies on the lumazine synthase/riboflavin synthase complex of Bacillus subtilis: crystal structure analysis of reconstituted, icosahedral beta-subunit capsids with bound substrate analogue inhibitor at 2.4 A resolution." J Mol Biol 253(1);151-67. PMID: 7473709
Arifuzzaman06: Arifuzzaman M, Maeda M, Itoh A, Nishikata K, Takita C, Saito R, Ara T, Nakahigashi K, Huang HC, Hirai A, Tsuzuki K, Nakamura S, Altaf-Ul-Amin M, Oshima T, Baba T, Yamamoto N, Kawamura T, Ioka-Nakamichi T, Kitagawa M, Tomita M, Kanaya S, Wada C, Mori H (2006). "Large-scale identification of protein-protein interaction of Escherichia coli K-12." Genome Res 16(5);686-91. PMID: 16606699
Baba06: Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M, Datsenko KA, Tomita M, Wanner BL, Mori H (2006). "Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection." Mol Syst Biol 2;2006.0008. PMID: 16738554
Bacher97: Bacher A, Richter G, Ritz H, Eberhardt S, Fischer M, Krieger C (1997). "Biosynthesis of riboflavin: GTP cyclohydrolase II, deaminase, and reductase." Methods Enzymol 280;382-9. PMID: 9211333
Chi09: Chi A, Rhee S (2009). "The functional annotation of Arabidopsis protein sequences was performed by BLAST queries against a reference set of experimentally verified enzymes. For each Arabidopsis sequence, the enzymatic activity of the top BLAST hit (or hits if they had equivalent E-values) was assigned to the protein if its E-value fell below a specific E-value threshold established for the corresponding enzymatic activity. Note: The annotation thresholds were established by doing a self BLAST of the reference enzyme dataset. For each enzymatic activity represented by multiple proteins, the mean E-value of all the correct hits generated by the self BLAST was selected as the cut-off. All of these means were averaged and used as the cut-off for assigning annotations for any enzymatic activities that were represented by a single protein in the reference dataset."
DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114
Eberhardt96: Eberhardt S, Richter G, Gimbel W, Werner T, Bacher A (1996). "Cloning, sequencing, mapping and hyperexpression of the ribC gene coding for riboflavin synthase of Escherichia coli." Eur J Biochem 242(3);712-9. PMID: 9022701
Fischer02: Fischer M, Romisch W, Schiffmann S, Kelly M, Oschkinat H, Steinbacher S, Huber R, Eisenreich W, Richter G, Bacher A (2002). "Biosynthesis of riboflavin in archaea studies on the mechanism of 3,4-dihydroxy-2-butanone-4-phosphate synthase of Methanococcus jannaschii." J Biol Chem 277(44);41410-6. PMID: 12200440
Fischer04: Fischer M, Schott AK, Romisch W, Ramsperger A, Augustin M, Fidler A, Bacher A, Richter G, Huber R, Eisenreich W (2004). "Evolution of vitamin B2 biosynthesis. A novel class of riboflavin synthase in Archaea." J Mol Biol 343(1);267-78. PMID: 15381435
Fischer05: Fischer M, Haase I, Feicht R, Schramek N, Kohler P, Schieberle P, Bacher A (2005). "Evolution of vitamin B2 biosynthesis: riboflavin synthase of Arabidopsis thaliana and its inhibition by riboflavin." Biol Chem 386(5);417-28. PMID: 15927885
Fischer05a: Fischer M, Romisch W, Illarionov B, Eisenreich W, Bacher A (2005). "Structures and reaction mechanisms of riboflavin synthases of eubacterial and archaeal origin." Biochem Soc Trans 33(Pt 4);780-4. PMID: 16042598
GarciaRamirez95: Garcia-Ramirez JJ, Santos MA, Revuelta JL (1995). "The Saccharomyces cerevisiae RIB4 gene codes for 6,7-dimethyl-8-ribityllumazine synthase involved in riboflavin biosynthesis. Molecular characterization of the gene and purification of the encoded protein." J Biol Chem 270(40);23801-7. PMID: 7559556
Gerdes02: Gerdes SY, Scholle MD, D'Souza M, Bernal A, Baev MV, Farrell M, Kurnasov OV, Daugherty MD, Mseeh F, Polanuyer BM, Campbell JW, Anantha S, Shatalin KY, Chowdhury SA, Fonstein MY, Osterman AL (2002). "From genetic footprinting to antimicrobial drug targets: examples in cofactor biosynthetic pathways." J Bacteriol 184(16);4555-72. PMID: 12142426
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