Lessons from Biochemical Mechanisms

Enzyme mechanisms can often avoid high-energy, unstable cationic or anionic intermediates that increase the reaction barrier. Triosephosphate isomerase catalyzes the tautomerization of the achiral dihydroxy acetone phosphate (DHAP) to f -glyceraldehyde-3-phosphate (G3P) by the mechanism shown below. Not only does the push-pull mechanism avoid forming a highly basic enolate, but the binding mode of DHAP determines which face of the enediol will be protonated in the second step, and therefore 

Enzymes, in addition to providing hydrogen bonding to anions formed, use electrostatic catalysis to polarize the reactant and compensate for a charge formed on the substrate as it reacts. Although it may be difficult to protonate a carbonyl (pA a = 7) at 

There are many other uses for metals in biochemistry for binding of oxygen (hemoglobin), as templates bringing reactants together (aconitase), for electron transport (cytochrome c), for redox reactions (P450), for organometaUics (vitamin B12), and more. 

Aldolase is an example of an enzyme that uses electrophilic covalent catalysis. The amine of an active site lysine forms an imine (Section 10.5.2) with the carbonyl of fructose-1,6-bisphosphate. This more reactive imine electron sink allows a reverse aldol reaction to occur via the less basic enamine rather than the more basic enolate ion. Tautomerization of the resulting enamine to an imine, then hydrolysis, releases DHAP and returns the enzyme active site lysine to the free anime, ready for the next cycle. 

Enzymatic catalysis lowers AG to accelerate the reaction rate, but does not affect the AG° that controls the position of equilibrium. However, cells also have an elegant ability to overcome an unfavorable equilibrium by coupling an endothermic reaction with exothermic ATP hydrolysis. For example, the reaction of acetate with coenzyme A (CoASH) giving acetyl CoA is uphill by about 7 kcal/mol. The hydrolysis of ATP to ADP and phosphate is downhill by about the same amount. By coupling these two reactions shown below for acyl-CoA synthetase, the cell achieves a total AG° of almost 0 for a ATgq of about 1. The phosphorylation of acetate by ATP improves the leaving group for the second reaction with CoASH. There are many enzymes whose catalytic process remains a mystery enzymes still have much to teach us about reaction mechanisms. 

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Among the most important lessons learned from these studies is that exposures to toxicants can yield a wide spectrum of neurotoxic effects ranging from overt encephalopathy and severe mental retardation to subtle deficits in sensory, motor, and cognitive functions. These effects depend on the timing, magnitude, and duration of exposure and many other factors (Mendola et al., 2002). Multiple mechanisms, target molecules, biochemical pathways, and cellular processes may explain the assembly of effects attributable to exposures to these substances. 

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