Abstract
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.
Highlights
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-dimethyl8-ribityllumazine synthase catalyzing the penultimate step in riboflavin biosynthesis
Recent studies have identified a pentacyclic intermediate in the reaction trajectories of riboflavin synthases of an eubacterium, Escherichia coli, and an Archaeon, M. jannaschii which have been designated as Compound Q and Compound Q, respectively (Fig. 7)
The intermediate Q produced by the eubacterial enzyme can serve as a kinetically competent substrate for the eubacterial but not for the archaeal enzyme; the intermediate Q produced by the archaeal enzyme is a kinetically competent substrate for the archaeal enzyme and not for the eubacterial enzyme [39]
Summary
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-dimethyl8-ribityllumazine synthase catalyzing the penultimate step in riboflavin biosynthesis. 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); that reaction involves the transfer of a four-carbon moiety between two DMRL molecules serving as donor and acceptor, respectively (10 –13).
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