title: Sweet siblings with different faces: the mechanisms of FBP and F6P aldolase, transaldolase, transketolase and phosphoketolase revisited in light of recent structural data.
abstract: Nature has evolved different strategies for the reversible cleavage of ketose phosphosugars as essential metabolic reactions in all domains of life. Prominent examples are the Schiff-base forming class I FBP and F6P aldolase as well as transaldolase, which all exploit an active center lysine to reversibly cleave the C3-C4 bond of fructose-1,6-bisphosphate or fructose-6-phosphate to give two 3-carbon products (aldolase), or to shuttle 3-carbon units between various phosphosugars (transaldolase). In contrast, transketolase and phosphoketolase make use of the bioorganic cofactor thiamin diphosphate to cleave the preceding C2-C3 bond of ketose phosphates. While transketolase catalyzes the reversible transfer of 2-carbon ketol fragments in a reaction analogous to that of transaldolase, phosphoketolase forms acetyl phosphate as final product in a reaction that comprises ketol cleavage, dehydration and phosphorolysis. In this review, common and divergent catalytic principles of these enzymes will be discussed, mostly, but not exclusively, on the basis of crystallographic snapshots of catalysis. These studies in combination with mutagenesis and kinetic analysis not only delineated the stereochemical course of substrate binding and processing, but also identified key catalytic players acting at the various stages of the reaction. The structural basis for the different chemical fates and lifetimes of the central enamine intermediates in all five enzymes will be particularly discussed, in addition to the mechanisms of substrate cleavage, dehydration and ring-opening reactions of cyclic substrates. The observation of covalent enzymatic intermediates in hyperreactive conformations such as Schiff-bases with twisted double-bond linkages in transaldolase and physically distorted substrate-thiamin conjugates with elongated substrate bonds to be cleaved in transketolase, which probably epitomize a canonical feature of enzyme catalysis, will be also highlighted.
authors.affiliation: Göttingen Center for Molecular Biosciences, Georg-August University Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany. Electronic address: ktittma@gwdg.de.
authors.forename: Kai
authors.initials: K
authors.lastname: Tittmann
mesh_terms: D000446:Aldehyde-Lyases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D005634:Fructose-Bisphosphate Aldolase / Q000737:chemistry / Q000378:metabolism*; D005636:Fructosephosphates / Q000378:metabolism; D006801:Humans; D011487:Protein Conformation; D013379:Substrate Specificity; D014153:Transaldolase / Q000737:chemistry / Q000378:metabolism*; D014174:Transketolase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005636:Fructosephosphates; C027618:fructose-6-phosphate; D014174:Transketolase; D014153:Transaldolase; D000446:Aldehyde-Lyases; D005634:Fructose-Bisphosphate Aldolase; C022367:phosphoketolase
keywords: Aldolase; Bond cleavage; Catalysis; Crystallography; Enzyme mechanism; Intermediate; Phosphoketolase; Phosphosugar; Ring opening; Schiff base; Strain; Structure; Thiamin diphosphate; Transaldolase; Transketolase