Pteridine, XLIV. Über die Synthese und Struktur <i>N</i>‐8‐substituierter Pterine und Lumazine

Pfleiderer, Wolfgang; Mengel, Rudolf; Hemmerich, Peter

doi:10.1002/cber.19711040731

Cited by 45 publications

(14 citation statements)

References 16 publications

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“…However, at pD 2 [ Fig. l The assignment of the pterin in this solid as the 6-isomer is confirmed by the lack of exchange exhibited by the ring methyl group (δ 2.27) at pD 7 [28] . Thus both the UV/vis and NMR data for the crude solid product indicate that it is probably a compound Brought to you by | Purdue University Libraries Authenticated Download Date | 6/12/15 2:33 AM with a dihydropterin-like structure which is transformed into the oxidized pterin either by dilution or in acid conditions.…”

Section: ) Determination Of Appropriate Reaction Conditionssupporting

confidence: 67%

Approaches to the Preparation of 6- and 7-Methyl-8-Substituted Pterins: Part 1. The Effect of Reaction Conditions on Isomer Distribution and a Novel Approach to Isomer Separation

Ivery

Gready²

1992

Biological Chemistry Hoppe-Seyler

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A new approach to the preparation of 6-and 7-methyl-8-alkylpterins is reported. This procedure relies primarily on the separation of the isomers due to their different propensities to form adducts with hydrogensulfite. The primary synthesis of 6-methyl-8-propylpterin was achieved by the condensation of 2,5-diamino-6-(propylamino)pyrimidin-4(3//)-one with pyruvic aldehyde in the presence of NaHSOs at pH 4. This results in a solid product which was found to be > 98% pure 6-isomer in the form of the HSOf adduct. Further treatment by a simple procedure gave the final product as the pterin hydrochloride greater than 99.5% isomer pure.The 7-methyl isomer was obtained from the filtrate of the primary synthesis by a cation exchange Chromatographie procedure, again exploiting the different propensities of the two isomers to form adduct. The effect of reaction conditions and the nature of the 8-substituent on the proportions of the isomeric products produced by the above condensation reaction was investigated by a series of small scale syntheses. It was found that the proportion of the two isomeric products was dependent on the size of the 8-substituent and, to a lesser extent, the pH of the reaction mixture. For large 8-substituents such as n-propyl, isopropyl and 2-hydroxyethyl, 6-methyl isomer was the predominant product under all conditions. The presence of HSOf did not generate any significant regioselective effect toward further formation of 6-isomer but had either negligible effect on the product distribution or increased the amount of 7-isomer formed. For the small methyl 8-substituent, the major product in the absence of HSOf was found to be 7-isomer at all pH values. However, in the presence of HSOf the major product became the 6-isomer. Α Ή-ΝΜΚ study of the nature of pyruvic aldehyde in acidic water solution is reported which shows that pyruvic aldehyde exists primarily as the monohydrated geminal ketodiol with a lesser proportion of the bishydrated vicinal diol. No free aldehyde was observed by Ή-ΝΜΚ. The implications of these findings and the product distribution experiments are discussed in relation to the mechanism of the reaction and the role of HSOf within this mechanism.

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Section: ) Determination Of Appropriate Reaction Conditionssupporting

confidence: 67%

Approaches to the Preparation of 6- and 7-Methyl-8-Substituted Pterins: Part 1. The Effect of Reaction Conditions on Isomer Distribution and a Novel Approach to Isomer Separation

Ivery

Gready²

1992

Biological Chemistry Hoppe-Seyler

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“…Early work by Plaut, Wood, Pfeiderer, and their respective groups had established that the position 7 methyl group of DMRL is acidic with a pK a around 9 (41). This unusually high CH acidity has been attributed to the resonance stabilization of the lumazine anion (13,(42)(43)(44). The authors quoted above have proposed several variations on a common theme for the transformation of DMRL into riboflavin (11,39,40,45,46).…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of an Archaeal Pentameric Riboflavin Synthase in Complex with a Substrate Analog Inhibitor

Ramsperger

Augustin

Schott

et al. 2006

Journal of Biological Chemistry

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Whereas eubacterial and eukaryotic riboflavin synthases form homotrimers, archaeal riboflavin synthases from Methanocaldococcus jannaschii and Methanothermobacter thermoautrophicus are homopentamers with sequence similarity to the 6,7-dimethyl-8-ribityllumazine synthase catalyzing the penultimate step in riboflavin biosynthesis. Recently it could be shown that the complex dismutation reaction catalyzed by the pentameric M. jannaschii riboflavin synthase generates riboflavin with the same regiochemistry as observed for trimeric riboflavin synthases. Here we present crystal structures of the pentameric riboflavin synthase from M. jannaschii and its complex with the substrate analog inhibitor, 6,7-dioxo-8-ribityllumazine. The complex structure shows five active sites located between adjacent monomers of the pentamer. Each active site can accommodate two substrate analog molecules in anti-parallel orientation. The topology of the two bound ligands at the active site is well in line with the known stereochemistry of a pentacyclic adduct of 6,7-dimethyl-8-ribityllumazine that has been shown to serve as a kinetically competent intermediate. The pentacyclic intermediates of trimeric and pentameric riboflavin synthases are diastereomers.Riboflavin (vitamin B 2 ) serves as the precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), essential cofactors for several oxidoreductases that are indispensable in most living cells. The work on riboflavin biosynthesis in microorganisms has been covered extensively in recent reviews (1-4). Riboflavin is biosynthesized in plants, many bacteria, and in fungi but not in animals. Therefore, enzymes of this pathway have been proposed to be attractive targets for antimicrobial strategies (5-7).In the final steps of the biosynthetic pathway, lumazine synthase (LS) catalyzes the condensation of the pyrimidinedione (1) with 3,4-dihydroxy-2-butanone-4-phosphate (2) to release water, inorganic phosphate and 6,7-dimethyl-8-ribityllumazine (DMRL) 7 (8, 9), and riboflavin synthase (RS) catalyzes a dismutation of DMRL (3) affording riboflavin (4) and 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione (1) (Fig. 1); more specifically, that reaction involves the transfer of a four-carbon moiety between two DMRL molecules serving as donor and acceptor, respectively (10 -13). Both reactions are thermodynamically irreversible (9, 14) and can proceed in the absence of a catalyst (11,(15)(16)(17).LS from fungi are c 5 -symmetric homopentamers, whereas the enzymes from plants, Archaea, and most eubacteria studied are 532 symmetric capsids of 60 identical subunits, which are best described as dodecamers of pentamers. The subunit folding patterns of pentameric and icosahedral LS are similar. In Bacillaceae, lumazine synthase and riboflavin synthase form a complex comprising an icosahedral capsid of 60 lumazine synthase subunits and a core of three riboflavin synthase subunits; historically, these unusual enzyme complexes were designated heavy riboflavin synthase (18,19). Riboflavin syn...

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“…0.5%. Predominantly, however, the mixture contains several tricyclic molecular species arising by the nucleophilic attack of one of the side chain hydroxy groups on the ring carbon 7 [23][24][25][26]. The acidic protons of the position 7 methyl group are easily exchanged with solvent water [15,23,27], and this exchange is accelerated by riboflavin synthase [15].…”

Section: Scheme 1 the Biosynthesis Of Riboflavin And Flavocoenzymesmentioning

confidence: 99%

Structures and reaction mechanisms of riboflavin synthases of eubacterial and archaeal origin

Fischer

Römisch

Illarionov

et al. 2005

Biochemical Society Transactions

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The biosynthesis of one riboflavin molecule requires one molecule of GTP and two molecules of ribulose 5-phosphate as substrates. GTP is hydrolytically opened, converted into 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione by a sequence of deamination, side chain reduction and dephosphorylation. Condensation with 3,4-dihydroxy-2-butanone 4-phosphate obtained from ribulose 5-phosphate leads to 6,7-dimethyl-8-ribityllumazine. The dismutation of 6,7-dimethyl-8-ribityllumazine catalysed by riboflavin synthase produces riboflavin and 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione. A pentacyclic adduct of two 6,7-dimethyl-8-ribityllumazines has been identified earlier as a catalytically competent reaction intermediate of the Escherichia coli enzyme. Acid quenching of reaction mixtures of riboflavin synthase of Methanococcus jannaschii, devoid of similarity to riboflavin synthases of eubacteria and eukaryotes, afforded a compound whose optical absorption and NMR spectra resemble that of the pentacyclic E. coli riboflavin synthase intermediate, whereas the CD spectra of the two compounds have similar envelopes but opposite signs. Each of the compounds could serve as a catalytically competent intermediate for the enzyme by which it was produced, but not vice versa. All available data indicate that the respective pentacyclic intermediates of the M. jannaschii and E. coli enzymes are diastereomers. Whereas the riboflavin synthase of M. jannaschii is devoid of similarity with those of eubacteria and eukaryotes, it has significant sequence similarity with 6,7-dimethyl-8-ribityllumazine synthases catalysing the penultimate step of riboflavin biosynthesis. 6,7-Dimethyl-8-ribityllumazine synthase and the archaeal riboflavin synthase appear to have diverged early in the evolution of Archaea from a common ancestor.

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Pteridine, XLIV. Über die Synthese und Struktur N‐8‐substituierter Pterine und Lumazine

Cited by 45 publications

References 16 publications

Approaches to the Preparation of 6- and 7-Methyl-8-Substituted Pterins: Part 1. The Effect of Reaction Conditions on Isomer Distribution and a Novel Approach to Isomer Separation

Approaches to the Preparation of 6- and 7-Methyl-8-Substituted Pterins: Part 1. The Effect of Reaction Conditions on Isomer Distribution and a Novel Approach to Isomer Separation

Crystal Structure of an Archaeal Pentameric Riboflavin Synthase in Complex with a Substrate Analog Inhibitor

Structures and reaction mechanisms of riboflavin synthases of eubacterial and archaeal origin

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