Anslyn pp. 489 – 536

p. 490 — “Why do we want to catalyze a reaction” — to speed it up.  That’s the way chemists think of catalysis, but pedagogically A & D really missed the boat.  Why does the body need catalysis?  Raising the temperature speeds up most reactions, but living things require enzymatic catalysis so the organism doesn’t fry in the process of performing the reactions of intermediary metabolism. You can set a cube of glucose on fire by holding a match to it — it burns quite nicely.  They should have said something to this effect. 

p. 493 — “To achieve catalysis, the catalyst must stabilize the transition state more than it stabilizes the ground state”.  The idea that the ground state and product state must also (italics) be stabilized by the catalyst wasn’t emphasized in the books I read years ago (it isn’t even in Voet’s biochemistry).  Otherwise you have essentially preformed transition states wandering around waiting for a catalyst to bind to them.  Physically impossible. Obvious once you think of it. 

p. 494 “Enzymes have evolved to execute their reactions within a specific time period appropriate for the metabolism of life”.   Tautologous at best.  Fortunately they recover when they flesh this out discussing perfect enzymes (p. 529).

p. 494  — The spatial temporal postulate — that catalysts work by getting (and keeping) the reactants together so they react — is so obvious that I’d never thought of it this way 

p. 495 — Eq. 9.3 should be Fig. 9.3

p. 505 — Organocatalysis — Nice to see one reason why MacMillan is the head of the Princeton chemistry department — stereochemical organic catalysis.  Clever ! ! ! !

p. 506 — The lysozyme example is interesting, but a more complete diagram showing how the saccharide fits into the active site would be more convincing.  Something pushing the CH2OH group wouldn’t work unless the bottom of the ring were sitting on something in the protein preventing it from moving.  

p. 507 — Interesting that the specific acid and the specific base differ from each other by TWO protons, unlike conventional acid base chemistry. 

p. 510 — specific acid and base catalysis — slick way to tell if they are actually occurring by plotting the log of the rate vs. pH (also logarithmic).

p. 516 — Well, it had to happen sooner or later, a poorly written and wordy section of Anslyn && Dougherty.  There’s a lot of huffing and puffing for some pretty simple chemistry and math.   Otherwise, the writing in the book is superb. 

p.520 — The libido rule — who would have thought a chemist would use sex to sell books.  It seems trivial and obvious (the rule that is) and unworthy of a name.  Sex is certainly out there on the net.  A post titled “The tail of RNA polymerase II and the limits of chemical explanation” has generated all sorts of pornographic spam.  Guess why.  

p. 523 – 529 —  The discussion of enzymes is quite good, particularly in making explicit all the assumptions of Michaelis Menten kinetics.  It is especially good in discussing what a perfect enzyme is, how selection has optimized the Km of enzymes to match the concentration of their substrates, and why this as efficient as an enzyme can be. 

        Nonetheless the discussion in this section could be improved.  A few points:     

        In their description of the Michaelis Menten model, they don’t mention that it assumes the product (P) leaves enzyme forever, never to get back to substrate.  This simply isn’t true for many enzymes.  This must be the case as enzymes don’t change the free energy of reactant or product.  If the free energies are close all you need is the law of mass action to reverse the effect of the enzyme.  Many physiologic pumps (notably neurotranmitter reuptake proteins) can be run in reverse, depending on the concentrations of substrate inside and outside the cell. 
    
        A&D  totally ignore the fact that physiologic enzyme concentration are are quite low and that it must be  this way.  The molecular mass of glucose 6 phosphatase with its 357 amino acid must be at least 30 kiloDaltons. Carbonic anhydrase, a perfect enzyme discussed in this section, has a molecular mass of 29 – 35 kiloDaltons (depending on which gene product you are talking about).   So that’s a minimum 29 kiloGram molecular mass —  which is physically impossible to dissolve in 1 kiloGram of water to obtain a 1 molar solution.  

       Wikipedia says that cytoplasmic protein concentration is quite high — about 200 milliGrams/milliLiter.  So even if all the protein in the cell were carbonic anhydrase, its concentration would be 200/29,000 = 6 milliMolar.  But of course, that would leave no room for anything else, and the genome is thought to code for 20,000 or so different proteins, so probably the actually cellular concentration of any given enzyme is at most .6 microMolar.  Of course, exceptions do exist — the protein concentration of hemoglobin in a red blood cells — which is essentially a bag of hemoglobin (no DNA with its transcription machinery, no ribosomes, no messenger RNA) — is about the maximum 5 milliMolar.

      p. 524 —  Vmax is k(cat) * [ Eo ] and is easily measured.  This immediately gives the  Michaelis Menten constant (Km) which is Vmax/2 (this is why Vmax is so useful).  They could have put this in instead of saying “there are several ways to measure k(cat) and Km, which we leave to a textbook devoted to biochemisty”.  

      p. 524 — According to Wikipedia  Michaelis Menton should be Michaelis Menten, for Maude Menten one of the first woman MDs in Canada.  Born in 1879, she got her MD in 1911 and her PhD at the University of Chicago.  At the time women were not allowed to do research in Canada  (and you thought Canada was always so enlightened) so she went to Germany where she began to work with Leonor Michaelis getting her PhD in 1916.  Michaelis Mentin is spelled correctly on p. 523.

       It’s a worthwhile exercise in dimensional analysis to figure out why the unit of the Michaelis Menten constant turns out to be the unit of concentration (e.g. Molar).  A first order rate constant is in units of seconds^-1, a second order rate constant is in unit of moles^-1 * seconds^-1.  Quick — is a reaction going to go more slowly or more rapidly with a numerically larger rate constant.  Answer: the larger for the same reason that you ski faster on a steeper hill.  

p. 526 — You’d better know what a ribbon diagram of a protein is before looking at figure 9.15

p. 529 — “Bimolecular diffusion rates in water at conventional temperatures are in the range of 10^8 – 10^9/Mole * second”  A fact worth remembering.  This is the maximum k1 can be in Michaelis Menten kinetics in the real world. 

       The description of a perfect enzyme is excellent and should be remembered.  It does show the utility of thinking and thinking hard about kinetics (despite all my snarky remarks about them throughout these notes).  

p. 530 — Perhaps when the book was written modifying antibodies to produce enzymes hadn’t been done yet.  The reference to the artifical cyclodextrin enzyme is 14 years old.  
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