Through Proper Channels

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Science  14 Dec 2001:
Vol. 294, Issue 5550, pp. 2251
DOI: 10.1126/science.294.5550.2251c

Tetrapyrroles are essential building blocks for respiration (hemes) and photosynthesis (chlorophylls). In plants and most prokaryotes, glutamyl-tRNA, besides being used in protein biosynthesis, is the starting point for synthesis of tetrapyrroles. The activated glutamate is reduced to glutamate-1-semialdehyde by the NADPH-dependent enzyme glutamyl-tRNA reductase (GluTR), and the semialdehyde then undergoes transamination by glutamate-1-semialdehyde aminomutase (GSAM), yielding the tetrapyrrole precursor 5-aminolevulinic acid.

Moser et al. describe the V-shaped structure of dimeric GluTR in complex with a substrate-like inhibitor and find that it supports the proposed mechanism of catalysis via a thioester intermediate. Reduction of the thioester to the semialdehyde would require movement of the distal NADPH-binding domain, and modeling the GluTR structure with a substrate glutamyl-tRNA reveals a shallow surface that could accommodate just such a tilted domain, which would bring the NADPH close to the glutamate-binding pocket. The reactive semialdehyde intermediate serves as a metabolic link between the enzymes GluTR and GSAM. The latter also forms a dimer, and that dimer can be modeled snugly into the cleft of the “V”. Strikingly, this complex reveals a conduit between the peripheral glutamate binding pocket in GluTR and the central active site in GSAM, enabling transfer of the semialdehyde without exposure to the aqueous environment.—VV

EMBO J.23, 6583 (2001).

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