Abstract
One of the most critical events in the origins of cellular life was the development of lipid membranes. Archaea use isoprenoid chains linked via ether bonds to sn-glycerol 1-phosphate (G1P), whereas bacteria and eukaryotes use fatty acids attached via ester bonds to enantiomeric sn-glycerol 3-phosphate. NAD(P)H-dependent G1P dehydrogenase (G1PDH) forms G1P and has been proposed to have played a crucial role in the speciation of the Archaea. We present here, to our knowledge, the first structures of archaeal G1PDH from the hyperthermophilic methanogen Methanocaldococcus jannaschii with bound substrate dihydroxyacetone phosphate, product G1P, NADPH, and Zn(2+) cofactor. We also biochemically characterized the enzyme with respect to pH optimum, cation specificity, and kinetic parameters for dihydroxyacetone phosphate and NAD(P)H. The structures provide key evidence for the reaction mechanism in the stereospecific addition for the NAD(P)H-based pro-R hydrogen transfer and the coordination of the Zn(2+) cofactor during catalysis. Structure-based phylogenetic analyses also provide insight into the origins of G1PDH.
Highlights
Archaea synthesize glycerol-based membrane lipids of unique stereochemistry, utilizing distinct enzymology
Phylogenetic and structure-based sequence analysis using the new archaeal glycerol 1-phosphate (G1P) dehydrogenase (G1PDH) structure confirms that G1PDHs are part of the larger structurally related superfamily containing four clades of metal- and NAD(P)H-dependent dehydrogenases (G1PDHs, glycerol dehydrogenases (GDHs), dehydroquinate synthases (DHQSs), and alcohol dehydrogenases (ADHs)) and provides insight into the origins of G1PDH
The distribution of G1PDHs, DHQSs, ADHs, and GDHs in Archaea and Bacteria suggests that at least one ancestral sequence for this metallodehydrogenase superfamily was present in the last universal common ancestor (LUCA) [50]
Summary
Archaea synthesize glycerol-based membrane lipids of unique stereochemistry, utilizing distinct enzymology. Results: The structure of sn-glycerol-1-phosphate dehydrogenase (G1PDH), the first step in archaeal lipid synthesis, was determined. Bacterial membranes consist of fatty acid esters with glycerol 3-phosphate, the stereochemistry of which contrasts with that of archaeal membranes based on isoprenoid ethers linked to sn-glycerol 1-phosphate (G1P).. The last universal common ancestor (LUCA) possessed genes for biosynthesis of both G1P isoprenoid and glycerol 3-phosphate fatty acyl lipid types, and the extant bacterial-archaeal differences are due to differential loss [10,11,12]. The LUCA did not have genetically encoded lipid biosynthesis, it might have had geochemically synthesized lipids, and the evolutionary invention of distinct bacterial and archaeal lipids occurred independently in the stem lineages that gave rise to the Achaea and Bacteria [3, 7, 13]. The first alternative predicts that both lipid synthetic pathways were early evolutionary inventions, whereas the second proposes that life arose within geochemically formed inorganic compartments
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