Inhibitors of the Giardia lamblia fructose 1,6-bisphosphate aldolase (GlFBPA), which transforms fructose 1,6-bisphosphate (FBP) to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, were designed based on 3-hydroxy-2-pyridone and 1,2-dihydroxypyridine scaffolds that position two negatively charged tetrahedral groups for interaction with substrate phosphate binding residues, a hydrogen bond donor to the catalytic Asp83, and a Zn 2+ binding group. The inhibition activities for the GlFBPA catalyzed reaction of FBP of the prepared alkyl phosphonate/phosphate substituted 3-hydroxy-2-pyridinones and a dihydroxypyridine were determined. The 3-hydroxy-2-pyridone inhibitor 8 was found to bind to GlFBPA with an affinity (K i = 14 μM) that is comparable to that of FBP (K m = 2 μM) or its inert analog TBP (K i = 1 μM). The X-ray structure of the GlFBPA-inhibitor 8 complex (2.3 Å) shows that 8 binds to the active site in the manner predicted by in silico docking with the exception of coordination with Zn 2+ . The observed distances and orientation of the pyridone ring O=C-C-OH relative to Zn 2+ are not consistent with a strong interaction. To determine if Zn 2+ coordination occurs in the GlFBPA-inhibitor 8 complex in solution, EXAFS spectra were measured. A four coordinate geometry comprised of the three enzyme histidine ligands and an oxygen atom from the pyridone ring O=C-C-OH was indicated. Analysis of the Zn 2+ coordination geometries in recently reported structures of class II FBPAs suggests that strong Zn 2+ coordination is reserved for the enediolate-like transition state, accounting for minimal contribution of Zn 2+ coordination to binding of 8 to GlFBPA.

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Amino acids U 0400Observations Made in Exploring a Pyridinium Salt Photochemical Approach to the Synthesis of (+)-Lactacystin. -The key step in the synthesis of (+)-lactacystin (V), a biologically interesting proteasome inhibitor, involves photocyclization of a cyclopenta-fused pyridinium salt using the newly synthesized compound (I) as model substrate. Especially the stereoselective formation of the tricyclic carbamate (IV) is described as potentially compatible with the general strategy. -(ZHOU, J.; GONG, M.; MARIANO*, P. S.; YOON, U. C.; Bull. Korean Chem. Soc. 29 (2008) 1, 89-93; Dep. Chem. Chem. Biol., Univ. N. Mex., Albuquerque, NM 87131, USA; Eng.) -H. Haber 23-188

Confidence bands in nonparametric regression have been studied for a long time with data assumed to be generated from independent and identically distributed (iid) random variables. The methods and theoretical results for iid data, however, do not directly apply to data from stratified multistage samples. In this paper, we extend the confidence bands introduced by Zhang and Lu (2008) for iid case to complex surveys based on an entirely data-driven procedure; the proposed confidence bands incorporate both the sampling weights and the kernel weights. Simulation studies show that the proposed method works well.