title: Dihydrodipicolinate Synthase: Structure, Dynamics, Function, and Evolution.
abstract: Enzymes are usually comprised of multiple subunits and more often than not they are made up of identical subunits. In this review we examine lysine biosynthesis and focus on the enzyme dihydrodipicolinate synthase in terms of its structure, function and the evolution of its varied number of subunits (quaternary structure). Dihydrodipicolinate synthase is the first committed step in the biosynthesis of lysine, which occurs naturally in plants, bacteria, archaea and fungi, but is not synthesized in mammals. In bacteria, there have been four separate pathways identified from tetrahydrodipicolinate to meso-diaminopimelate, which is the immediate precursor to lysine. Dihydrodipicolinate synthases from many bacterial and plant species have been structurally characterised and the results show considerable variability with respect to their quaternary structure, hinting at their evolution. The oligomeric state of the enzyme plays a key role, both in catalysis and in the allosteric regulation of the enzyme by lysine. While most bacteria and plants have tetrameric enzymes, where the structure of the dimeric building blocks is conserved, the arrangement of the dimers differs. We also review a key development in the field, namely the discovery of a human dihydrodipicolinate synthase-like enzyme, now known as 4-hydroxy-2-oxoglutarate aldolase . This discovery complicates the rationale underpinning drug development against bacterial dihydrodipicolinate synthases, since genetic errors in 4-hydroxy-2-oxoglutarate aldolase cause the disease Primary Hyperoxaluria Type 3 and therefore compounds that are geared towards the inhibition of bacterial dihydrodipicolinate synthase may be toxic to mammalian cells.
authors.affiliation: Biomolecular Interaction Centre and School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, 8041, New Zealand.
authors.forename: F
authors.initials: F
authors.lastname: Grant Pearce
authors.affiliation: Thomas H. Gosnell School of Life Sciences, Rochester Institute of Technology, Rochester, NY, USA.
authors.forename: André O
authors.initials: AO
authors.lastname: Hudson
authors.affiliation: School of Biological Sciences & Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
authors.forename: Kerry
authors.initials: K
authors.lastname: Loomes
authors.affiliation: Biomolecular Interaction Centre and School of Biological Sciences, University of Canterbury, Private Bag 4800, Christchurch, 8041, New Zealand. renwick.dobson@canterbury.ac.nz.|Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, VIC, 3010, Australia. renwick.dobson@canterbury.ac.nz.
authors.forename: Renwick C J
authors.initials: RCJ
authors.lastname: Dobson
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D006801:Humans; D006836:Hydro-Lyases / Q000737:chemistry* / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism
chemical_list: D006836:Hydro-Lyases; C020040:4-hydroxy-tetrahydrodipicolinate synthase; D008239:Lysine
keywords: 4-Hydroxy-2-oxoglutarate aldolase; Dihydrodipicolinate synthase; Lysine biosynthesis