V-shaped structure of glutamyl-tRNA reductase, the first enzyme of tRNA-dependent tetrapyrrole biosynthesis

Processes vital to life such as respiration and photosynthesis critically d epend on the availability of tetrapyrroles including hemes and chlorophylls . tRNA-dependent catalysis generally is associated with protein biosynthesi s. An exception is the reduction of glutamyl-tRNA to glutamate-1-semialdehy de by the enzyme glutamyl-tRNA reductase. This reaction is the indispensabl e initiating step of tetrapyrrole biosynthesis in plants and most prokaryot es. The crystal structure of glutamyl-tRNA reductase from the archaeon Meth anopyrus kandleri in complex with the substrate-like inhibitor glutamycin a t 1.9 Angstrom resolution reveals an extended yet planar V-shaped dimer. Th e well defined interactions of the inhibitor with the active site support a thioester-mediated reduction process. Modeling the glutamyl-tRNA onto each monomer reveals an extensive protein-tRNA interface. We furthermore propos e a model whereby the large void of glutamyl-tRNA reductase is occupied by glutamate-1-semialdehyde-1,2-mutase, the subsequent enzyme of this pathway, allowing for the efficient synthesis of 5-aminolevulinic acid, the common precursor of all tetrapyrroles.