Probable reaction mechanisms of flavokinase and FAD synthetase from rat liver

Yamada, Yukiko; Merrill, Alfred H.; McCormick, Donald B.

doi:10.1016/0003-9861(90)90240-y

Cited by 63 publications

(63 citation statements)

References 25 publications

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“…Because riboflavin and FMN are interconvertible (37)(38)(39)(40), as are PLP and PL (41,42), and PA is formed from PL, we calculated the sum of riboflavin and FMN as an index for vitamin B2 status and the sum of PLP, PL, and PA as an index of vitamin B6 status. In the present study, these sums of B2 and B6 vitamers are therefore considered as the main exposure variables for vitamin B2 and B6 status, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Although individual vitamin B2 and B6 species reflect vitamin B2 (51) and B6 (47) status, there is no clear consensus as to which vitamin specie is the best marker. We also used the sum of the individual species as indices of vitamin B2 and B6 status because the B2 species (37)(38)(39)(40) and the B6 species (41,42) are interconvertible, and the plasma concentrations are positively correlated, as shown here and by others (44).…”

Section: Methodsmentioning

confidence: 99%

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Vitamins B2 and B6 and Genetic Polymorphisms Related to One-Carbon Metabolism as Risk Factors for Gastric Adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition

Eussen

Vollset

Hustad

et al. 2010

Cancer Epidemiology, Biomarkers &Amp; Prevention

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B vitamins and polymorphisms in genes coding for enzymes involved in one-carbon metabolism may affect DNA synthesis and methylation and thereby be implicated in carcinogenesis. Previous data on vitamins B2 and B6 and genetic polymorphisms other than those involving MTHFR as risk factors for gastric cancer (GC) are sparse and inconsistent. In this case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort, cases (n = 235) and controls (n = 601) were matched for study center, age, sex, and time of blood sampling. B2 and B6 species were measured in plasma, and the sum of riboflavin and flavin mononucleotide was used as the main exposure variable for vitamin B2 status, whereas the sum of pyridoxal 5′-phosphate, pyridoxal, and 4-pyridoxic acid was used to define vitamin B6 status. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks for GC risk were calculated with conditional logistic regression, adjusted for Helicobacter pylori infection status and smoking status. Adjusted relative risks per quartile (95% confidence interval, P trend ) were 0.85 (0.72-1.01, 0.06) for vitamin B2 and 0.78 (0.65-0.93, <0.01) for vitamin B6. Both relations were stronger in individuals with severe chronic atrophic gastritis. The polymorphisms were not associated with GC risk and did not modify the observed vitamin-cancer associations. In summary, results from this large European cohort study showed an inverse association between vitamin B2 and GC risk, which is borderline significant, and a significant inverse association between vitamin B6 and GC risk. Cancer Epidemiol Biomarkers Prev; 19(1); 28-38. ©2010 AACR.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Vitamins B2 and B6 and Genetic Polymorphisms Related to One-Carbon Metabolism as Risk Factors for Gastric Adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition

Eussen

Vollset

Hustad

et al. 2010

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Two groups of RF kinases are recognized. One group is represented in fungi, plants, animals, archaea, and (rarely) eubacteria by monofunctional RF kinase proteins (10,26,73,211,214,289,387,390,458,537). The structures of S. pombe and human RF kinases showed a novel family of phosphoryl-transferring enzymes (26,211).…”

Section: Riboflavin Kinasementioning

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

324

272

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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.

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“…The formation of FAD depends on the sequential utilization of two molecules of ATP in reactions that first involve the riboflavin (flavokinase, EC 2.7.1.26) kinase-phosphorylation of riboflavin to form FMN and then FAD (EC 2.7.7.2) synthetase-catalyzed adenylylation of the latter to form FAD. The enzymes responsible for catalyzing the two steps have been purified from several sources (1)(2)(3)(4)(5)(6)(7)(8)(9). In Corynebacterium ammoniagenes and Bacillus subtilis, flavokinase and FAD synthetase co-purify and are present in a single, bifunctional flavokinase/FAD synthetase enzyme (7,10).…”

mentioning

confidence: 99%

Molecular Characterization of FMN1, the Structural Gene for the Monofunctional Flavokinase of Saccharomyces cerevisiae

Santos

Jiménez²,

Revuelta

2000

Journal of Biological Chemistry

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Riboflavin (vitamin B 2 ) serves as a precursor of the flavinnucleotide cofactors riboflavin monophosphate (FMN) 1 and flavin adenine dinucleotide (FAD). The formation of FAD depends on the sequential utilization of two molecules of ATP in reactions that first involve the riboflavin (flavokinase, EC 2.7.1.26) kinase-phosphorylation of riboflavin to form FMN and then FAD (EC 2.7.7.2) synthetase-catalyzed adenylylation of the latter to form FAD. The enzymes responsible for catalyzing the two steps have been purified from several sources (1-9). In Corynebacterium ammoniagenes and Bacillus subtilis, flavokinase and FAD synthetase co-purify and are present in a single, bifunctional flavokinase/FAD synthetase enzyme (7, 10). To date, a large number of homologs to the bifunctional flavokinase/FAD synthetase ribC gene of B. subtilis have been identified in archaea and eubacteria, indicating that this type of gene organization is common in prokaryotes. In contrast, both enzymatic activities have been purified separately in eukaryotic organisms (1,6,8). In mammalian tissues, the smaller flavokinase (1) is readily separable from the larger FAD synthetase (3). In the yeast Saccharomyces cerevisiae, the gene encoding a monofunctional FAD synthetase (FAD1) has recently been cloned as an extragenic suppressor of a respiratory deficient pet mutant (11). However, the gene encoding flavokinase in yeast as well as in the rest of eukaryotic organisms remains to be identified.The formation of holo-flavoproteins, by binding of the coenzyme to the apo-protein, depends on the availability of the cognate flavocoenzyme. It is known that most cell flavoproteins are located in the mitochondria but little is known about the subcellular distribution of the enzymes involved in flavin metabolism. It has been described that flavokinase is a cytosolic enzyme in plant and mammalian tissues (4, 6) and the synthesis of FMN and FAD occurs in hepatocyte cytosol (12). However, the synthesis of both flavocoenzymes from externally added riboflavin by isolated mitochondria from rat liver has been also reported (13). Whereas it has been determined that the synthesis of riboflavin occurs in the cytosol of S. cerevisiae cells (14, 15), the exact location of the synthesis of FMN and FAD and their compartmentation is controversial in this organism. It has been reported that yeast mitochondria do not contain FAD synthetase and that a specific mitochondrial carrier protein, Flx1p, is involved in flavin transport across the mitochondrial membrane (16). However, it has also been described that FMN and FAD synthesis occurs in isolated yeast mitochondria (17) and that yeast cells overexpressing the FAD1 gene show mitochondrial FAD synthetase activity (11).Homeostasis of flavin coenzymes is achieved by an intricate interplay of the different enzymes in the pathway responding to regulators (18), by organelle compartmentation (11,19), and by altered susceptibility of holo-and apo-flavoproteins to proteolytic digestion (20). Since yeast and other eukaryotes share the...

show abstract

Probable reaction mechanisms of flavokinase and FAD synthetase from rat liver

Cited by 63 publications

References 25 publications

Vitamins B2 and B6 and Genetic Polymorphisms Related to One-Carbon Metabolism as Risk Factors for Gastric Adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition

Vitamins B2 and B6 and Genetic Polymorphisms Related to One-Carbon Metabolism as Risk Factors for Gastric Adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition

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

Molecular Characterization of FMN1, the Structural Gene for the Monofunctional Flavokinase of Saccharomyces cerevisiae

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