Richard D. Gandour

Transition States of Biochemical Processes

1 * Scope and Limitations of the Concept of the Transition State.- 2 * Catalytic Power and Transition-State Stabilization.- 3 * Quantum-Mechanical Approaches to the Study of Enzymic Transition States and Reaction Paths.- 4 * Primary Hydrogen Isotope Effects.- 5 * Secondary Hydrogen Isotope Effects.- 6 * Solvent Hydrogen Isotope Effects.- 7 * Heavy-Atom Isotope Effects in Enzyme-Catalyzed Reactions.- 8 * Magnetic-Resonance Approaches to Transition-State Structure.- 9 * Mapping Reaction Pathways from Crystallographic Data.- 10 * Transition-State Properties in Acyl and Methyl Transfer.- 11 * Transition States for Hydrolysis of Acetals, Ketals, Glycosides, and Glycosylamines.- 12 * Decarboxylations of ?-Keto Acids and Related Compounds.- 13 * The Mechanism of Phosphoryl Transfer.- 14 * Intramolecular Reactions and the Relevance of Models.- 15 * Transition-State Affinity as a Basis for the Design of Enzyme Inhibitors.- 16 * Transition-State Theory and Reaction Mechanism in Drug Action and Drug Design.- Author Index.

On the importance of orientation in general base catalysis by carboxylate

The carboxylate group serves as a general-base catalyst in numerous chemical and enzymatic reactions. The importance of the direction in which the proton is transferred to the carboxylate is discussed. syn (on the same side of the CO bond as the forming CO) protonation is estimated to be 104-fold more favorable than anti protonation. To date, in the models studied where intramolecular reactions involve carboxylate, only anti protonation can occur. In these intramolecular models the catalytic efficiency of a carboxylate group may be underestimated due to this inability to achieve an optimal orientation for protonation; whereas for enzymatic reactions involving carboxylate side chains, structural studies support mechanisms involving syn protonation.

Carnitine acetyltransferase: A review of its biology, enzymology, and bioorganic chemistry

Abstract The review begins with brief introductory remarks about the significance of carnitine. This is followed by a historical section on its discovery and function, ending with a listing of carnitine-dependent enzymes. Carnitine acetyltransferase then becomes the entire focus of the review. The ubiquity of the protein in tissues and organelles is emphasized in an initial section. A discussion of its enzymology follows, beginning with physical properties and kinetics and ending with substrate and inhibitor specificities. The review concludes with a discussion of proposed molecular mechanisms.

Crystal structure of the 2:1 acetonitrile complex of 18-crown-6

Single crystal X-ray analysis of the 2:1 acetonitrile complex of 18-crown-6 is reported. Crystals of the complex are monoclinic,P21/n, witha=9.123(3),b=8.524(3),c=13.676(4) Å, β=104.68(3)°, andDc=1.118 g cm−3 forZ=2. The complex lies on a center of symmetry, with the crown in theD3d conformation. Methyl groups of the acetonitrile molecules have weak interactions with the crown oxygen atoms, and are tilted 31.7° from the hosts threefold axis. Methyl hydrogen atoms are rotationally disordered about the acetonitrile axis.

Crystal structures of carnitine and acetylcarnitine zwitterions: A structural hypothesis for mode of action

Abstract The solid-state structures of the zwitterionic forms of both carnitine and acetylcarnitine have been determined by single-crystal X-ray analysis. The crystal structure of acetylcarnitine reveals a different backbone conformation from that of carnitine. The conformational differences observed for carnitine and acetylcarnitine are more a consequence of steric than electrostatic effects. A detailed comparison is made between the zwietterionic structures and previously published hydrochloride salts. The effect of charge distribution on conformation is discussed. The zwitterionic structures do not exhibit enhanced electrostatic attraction between carboxylate and quaternary ammonium portions of the molecules. Finally, a hypothesis is presented for the mode of binding of carnitine (or acetylcarnitine) to the enzyme, carnitine acetyltransferase. Based on this model for binding, a speculative topographic description of the enzymatic mechanism is presented.

Synthesis and structure of stilbene crowns.

Abstract Syntheses of E - and Z -[a,e]-dibenzo-7,10,13-trioxacyclotrideca-1,3,5-triene, 1 (n=1) and E - and Z -[e,a]-dibenzo-7,10,13,16-tetraoxacyclohexadeca-1,3,5-triene, 1 (n=2) are described and the X-ray structure of E- 1 (n=1) is reported.

Molecules for intramolecular recognition. Synthesis and structures of diaryl- and arylnaphthylethynes

Abstract While synthesizing models for intramolecular recognition, a simple and efficient method for forming terminal arylethynes was developed and palladium-catalyzed coupling chemistry of alkynes with either aryl iodides or aryl triflates was used to form crowded disubstituted alkynes.

Active-site probes of carnitine acyltransferases. Inhibition of carnitine acetyltransferase by hemiacetylcarnitinium, a reaction intermediate analogue.

Hemiacetylcarnitinium (2S,6R:2R,65)-6-carboxymethyl-2-hydroxy-2,4,4- trimethylmorpholinium) chloride is a relatively potent competitive inhibitor (Ki = 0.89 mM) of pigeon breast carnitine acetyltransferase (CAT) and of the crude rat liver CAT (Ki = 4.72 mM) but is neither an inhibitor nor an effective substrate for purified rat liver carnitine palmitoyltransferase (CPT). It does not inhibit state 3 oxygen consumption in isolated hepatic mitochondria using palmitoyl-CoA or palmitoylcarnitine as substrates. This compound is a reaction intermediate analogue of the proposed tetrahedral intermediate for acetyl transfer between acetylcarnitine and CoASH. Because the hemiketal carbon is chiral, a suggestion is made that one of the enantiomers has the same relative configuration as the proposed tetrahedral intermediate.

Preparation of crystalline sodium norcarnitine: An easily handled precursor for the preparation of carnitine analogs and radiolabeled carnitine

A procedure by which crystalline sodium norcarnitine can be prepared in large quantities and high yields has been developed. Carnitine is selectively demethylated by thiophenoxide ion in N,N-dimethylethanolamine. The reactive thiophenoxide ion is generated in situ by addition of thiophenol to this basic reaction solvent. Hence, sodium thiophenoxide, which has been used in similar applications, but is difficult to prepare, can be avoided. Accordingly, reaction of (R,S)-carnitine followed by aqueous azeotropic distillation of byproducts as well as excess starting materials and then by neutralization with sodium hydroxide gave sodium norcarnitine in 89% yield. (R)-Carnitine gave 91% yield of (R)-norcarnitine zwitterion before neutralization. A method for the facile preparation of radiolabeled (R)-carnitine is also described. Thus, methylation of sodium norcarnitine with methyl iodide in methanolic acetone produced carnitine, which precipitated, and sodium iodide, which was soluble.

Complexation by N-(3,6,9-trioxadecyl)monoaza-12-crown-4 lariat ether: a “calabash” complex of a potassium cation by a synthetic macrocycle containing a total of only seven donor atoms

Abstract Structural and cation binding data for the title compound demonstrate that the large value of Ks results from complete K+ cation encapsulation by one nitrogen and six oxygen atoms despite the presence of a twelve-membered macroring.