Anticoccidial riboflavine antagonists

Graham, Donald W.; Brown, J. E.; Ashton, Wallace T.; Brown, R. D.; Rogers, Edward F.

doi:10.1007/bf01920129

Cited by 22 publications

(8 citation statements)

References 25 publications

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“…Since this flavokinase and FAD synthetase system is bacterial, it is risky to infer from it the properties of the avian and mammalian enzyme counterparts. However, it is possible that in the antimetabolite activities of some of these analogues (Graham et al, 1977;Otani, 1976) two very different loci of action are involved. Those analogues that lack the 5'-hydroxyl group may exert their effects by inhibiting the conversion of natural riboflavin to FMN and FAD, while those analogues with a ribityl side chain may be efficiently converted to FMN and FAD analogues, and then exert their in vivo effects after incorporation into redox-active flavoenzymes.…”

Section: Resultsmentioning

confidence: 99%

“…These analogues may be good steric replacements for natural flavins but not catalytic substitutes. Perhaps for this reason they are among the most potent anticoccidial agents (Graham et al, 1977) and the naturally occurring roseoflavin is found to be an effective antimetabolite (Otani, 1976). Also in this category we include 3-deazariboflavin, which, denoted by the open symbols in Figure 3, is considerably less reactive than its redox potential might suggest.…”

Section: Conclusion'mentioning

confidence: 99%

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Chemical and enzymic properties of riboflavin analogs

Walsh¹,

Fisher²,

Spencer³

et al. 1978

Biochemistry

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149

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The chemical and enzymatic properties of 26 analogues of riboflavin are presented. These analogues include both endo- and exocyclically substituted isoalloxazines with redox potentials from -370 to -128 mV. Physical and chemical data such as the electronic absorption spectra, pKas, and redox potentials of the analogues are presented and are discussed with respect to preferred tautomeric and resonance forms. Like riboflavin, most of the analogues are shown to be catalytic oxidants of dihydro-5-deazaflavins. Analogue binding to egg white binding apoprotein has been quantitated and serves to determine the origins of binding site specificity for this protein. Nearly all of the analogues that possess D-ribityl groups are found to be processed to the FAD level by the flavokinase/FAD synthetase system of Brevibacterium ammoniagenes. Most extensively studied are the reactivities of the analogues with the NAD(P)H:flavin oxidoreductase of Beneckea harveyi. Many of the analogues are substrates in this enzymatic redox reaction, and a linear free energy-rate relation (log Vmax vs. E0' of the analogue) is seen that parallels similar relationships in the nonenzymatic oxidation of dihydro-5-deazaflavins. This suggests a common mechanism for the reactions of such diverse flavins as riboflavin, 5-deazariboflavin, and 1-deazariboflavin.

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Section: Resultsmentioning

confidence: 99%

Section: Conclusion'mentioning

confidence: 99%

Chemical and enzymic properties of riboflavin analogs

Walsh¹,

Fisher²,

Spencer³

et al. 1978

Biochemistry

Self Cite

149

View full text Add to dashboard Cite

show abstract

“…Flavin Analogues-Preparation and Purification. The riboflavin level of each flavin analogue was prepared as cited: 5-deazariboflavin (O'Brien et al, 1970); 1-deazariboflavin (Ashton et al, 1977); 9-azariboflavin (Graham et al, 1977); 7-chloro-8-demethylriboflavin (Shunk et al, 1952);6methylriboflavin (Berezovskii & Rodionova, 1958). Flavokinase/FAD synthetase from Brevibacterium ammoniagenes was used in the syntheses of the various FAD analogues as reported in Spencer et al (1976).…”

Section: Methodsmentioning

confidence: 99%

Mechanistic studies on cyclohexanone oxygenase

Ryerson¹,

Ballou²,

Walsh³

1982

Biochemistry

216

110

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The bacterial flavoprotein monooxygenase carries out an oxygen insertion reaction on cyclohexanone, with ring expansion to form the seven-membered cyclic product epsilon-caprolactone, a transformation quite distinct from the phenol leads to catechol transformation carried out by the bacterial flavoprotein aromatic hydroxylases. Cyclohexanone oxygenase catalysis involves the four-electron of O2 at the expense of a two-electron oxidation of NADPH, concomitant with a two-electron oxidation of cyclohexanone to epsilon-caprolactone. NADPH oxidase activity is fully coupled with oxygen transfer to substrate. Steady-state kinetic assays demonstrate a ter-ter mechanism for this enzyme. Pre-steady-state kinetic assays demonstrate the participation of a 4a-hydroperoxyflavin intermediate during catalysis. In addition to its ketolactonizing activity, cyclohexanone oxygenase carries out S-oxygenation of thiane to thiane 1-oxide, a reaction which represents a nucleophilic displacement by the sulfur upon the terminal oxygen of the hydroperoxide. This is in contrast to cyclohexanone oxygenations where the flavin hydroperoxide acts as a nucleophile. In addition, a stable apoenzyme form is accessible and can be reconstituted with various FAD analogues with up to 100% recovery of enzyme activity. The accumulated results presented here support a Baeyer-Villiger rearrangement mechanism for the enzymatic oxygenation of cyclohexanone.

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“…Chemical syntheses resulted in a large collection of analogs of RF (30,33,249), and their biological activities have been studied in bacteria and animal models (152,250,279,515). Some of them possessed significant antibacterial or antiprotist activities.…”

Section: Other Natural Flavinsmentioning

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

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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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Anticoccidial riboflavine antagonists

Cited by 22 publications

References 25 publications

Chemical and enzymic properties of riboflavin analogs

Chemical and enzymic properties of riboflavin analogs

Mechanistic studies on cyclohexanone oxygenase

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

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