The outer leaflet of the outer membrane of the Gram-negative bacterium serves as a permeability barrier and is composed of lipopolysaccharide, also known as endotoxin. The membrane anchor of lipopolysaccharide is lipid A, the biosynthesis of which is essential for cell viability. The first committed step in lipid A biosynthesis is catalyzed by UDP-(3-O-(R-3-hydroxymyristoyl))-Nacetylglucosamine deacetylase (LpxC), a zinc-dependent deacetylase. Here we report the crystal structure of LpxC from Aquifex aeolicus, which reveals a new ␣؉ fold reflecting primordial gene duplication and fusion, as well as a new zinc-binding motif. The catalytic zinc ion resides at the base of an active-site cleft and adjacent to a hydrophobic tunnel occupied by a fatty acid. This tunnel accounts for the specificity of LpxC toward substrates and inhibitors bearing appropriately positioned 3-O-fatty acid substituents. Notably, simple inhibitors designed to target interactions in the hydrophobic tunnel bind with micromolar affinity, thereby representing a step toward the structure-based design of a potent, broad-spectrum antibacterial drug.
Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. The X-ray crystal structure of a fully active, truncated form of human arginase II complexed with a boronic acid transition state analogue inhibitor has been determined at 2.7 A resolution. This structure is consistent with the hydrolysis of l-arginine through a metal-activated hydroxide mechanism. Given that human arginase II appears to play a role in regulating l-arginine bioavailability to NO synthase in human penile corpus cavernosum smooth muscle, the inhibition of human arginase II is a potential new strategy for the treatment of erectile dysfunction [Kim, N. N., Cox, J. D., Baggio, R. F., Emig, F. A., Mistry, S., Harper, S. L., Speicher, D. W., Morris, S. M., Ash, D. E., Traish, A. M., and Christianson, D. W. (2001) Biochemistry 40, 2678-2688]. Since NO synthase is found in human clitoral corpus cavernosum and vagina, we hypothesized that human arginase II is similarly present in these tissues and functions to regulate l-arginine bioavailability to NO synthase. Accordingly, hemodynamic studies conducted with a boronic acid arginase inhibitor in vivo are summarized, suggesting that the extrahepatic arginase plays a role in both male and female sexual arousal. Therefore, arginase II is a potential target for the treatment of male and female sexual arousal disorders.
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