title: Theoretical exploration of the mechanism of riboflavin formation from 6,7-dimethyl-8-ribityllumazine: nucleophilic catalysis, hydride transfer, hydrogen atom transfer, or nucleophilic addition?
abstract: The cofactor riboflavin is biochemically synthesized by a constitutionally intricate process in which two molecules of 6,7-dimethyl-8-ribityllumazine react with each other to form one molecule of the cofactor and one molecule of 5-amino-6-(ribitylamino)uracil. Remarkably, this complex molecular transformation also proceeds non-enzymatically in boiling aqueous solution at pH 7.3. Four different mechanistic pathways for this transformation (nucleophilic catalysis, hydride transfer, hydrogen atom transfer, and a nucleophilic addition mechanism) have now been analyzed by density functional theory [M06-2X/def2-TZVPP/CPCM//M06-2X/6-31+G(d,p)/IEFPCM]. On the basis of these computational results, a so far unpublished nucleophilic addition mechanism is the lowest energy pathway yielding riboflavin. The previously proposed mechanism involving nucleophilic catalysis is higher in energy but is still a viable alternative for an enzyme-catalyzed process assisted by suitably positioned catalytic groups. Pathways involving the transfer of a hydride ion or of a hydrogen atom are predicted to proceed through higher energy transition states and intermediates.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Breugst
authors.forename: Albert
authors.initials: A
authors.lastname: Eschenmoser
authors.forename: K N
authors.initials: KN
authors.lastname: Houk
mesh_terms: D002384:Catalysis; D003500:Cyclization; D004735:Energy Transfer; D006859:Hydrogen / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D011522:Protons; D011621:Pteridines / Q000737:chemistry*; D012256:Riboflavin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D012997:Solvents; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D011522:Protons; D011621:Pteridines; D012997:Solvents; D013438:Sulfhydryl Compounds; D014867:Water; C001061:6,7-dimethyl-8-ribityllumazine; D006859:Hydrogen; D012256:Riboflavin