Chapter 29: The Organic Chemistry of Metabolic Pathways
Coupling, and what an anhydride actually buys
Two vocabularies meet in this chapter and it is worth separating them at the outset. Catabolism names the pathways that break large molecules down and release free energy; anabolism names those that build them up and consume it. Neither term is a synonym for oxidation or reduction, and both directions contain plenty of each. What the two have in common is that individual steps are frequently unfavorable on their own, and the cell has one general device for dealing with that. The chemistry itself is almost entirely familiar: the steps ahead are aldol additions, acyl substitutions,…
Two coenzymes, two different jobs
Every oxidation in this chapter happens without molecular oxygen. Oxygen appears only at the end of the electron-transport chain, downstream of all the bond making and breaking, so within the organic chemistry an oxidation means a transfer of hydrogen or electrons to a coenzyme that stands in for the oxidizing agent of a flask reaction. Nicotinamide adenine dinucleotide is the commoner of the two. Its structure is large, but only the pyridinium ring at one end is chemically active; the adenosine half and the two sugars serve as a recognition handle that enzymes grip. Oxidation of a secondary…
The thioester: one functional group, two useful properties
Acetyl coenzyme A is drawn in full once so that the proportions are clear, and after that it is written CoAS-CO-CH₃ or simply acetyl CoA. Of its fifty-odd atoms exactly one bond matters: the thioester joining an acetyl group to a sulfur atom. The rest - two amide linkages, a pyrophosphate bridge, a ribose bearing adenine and a further phosphate - is a recognition sequence that enzymes bind and that emerges from every reaction unchanged. The reason so much of metabolism runs through this one functional group is a single structural fact about sulfur. In an ordinary ester, an oxygen lone pair in…
Ten steps, six reaction types
Ten intermediates with unfamiliar names make glycolysis look harder than it is. Attaching a reaction type to each arrow reduces it to six kinds of chemistry, every one of which has appeared already. The first half spends energy. Hexokinase phosphorylates the C6 hydroxyl by nucleophilic substitution at the terminal phosphorus of ATP, and the charge on the product keeps the sugar inside the cell. Phosphoglucose isomerase then moves the carbonyl from C1 to C2 by way of a cis-enediol, an intermediate in which both carbons carry hydroxyls and a double bond runs between them; the C2 stereocenter of…
Losing carbon dioxide from the wrong side of a ketone
The conversion of pyruvate to acetyl coenzyme A is the junction between glycolysis and the citric acid cycle, and it is also the point at which the chapter's chemistry becomes least obvious. Three carbons enter, two leave as an acetyl group on coenzyme A, one leaves as carbon dioxide, and the carbon that remains has been oxidized from a ketone to a thioester. Setting the coenzymes aside, the difficulty is the decarboxylation. Decarboxylation is familiar from beta-keto acids, where it needs no catalyst at all. The requirement is geometric: the carboxyl group and a carbonyl three atoms away can…
One turn: an aldol addition, a relocation, and two decarboxylations
Two carbons enter the cycle as an acetyl group and two leave as carbon dioxide, and the four-carbon acceptor emerges exactly as it began. The bookkeeping conceals a subtlety worth stating early: isotopic labeling shows that the two carbons released in any given turn come from the oxaloacetate that accepted the acetyl group, not from the acetyl group itself, which stays in the cycle for at least one further turn. Citrate synthase begins the sequence and is a textbook case of an enzyme achieving with mild residues what a flask needs strong base for. Aspartate 375 removes an alpha proton from…
Four steps, repeated until the chain is gone
Triacylglycerols are hydrolyzed to fatty acids and glycerol before anything else happens. Glycerol is dealt with in two ordinary steps: a kinase phosphorylates one of its two equivalent primary hydroxyls, which are equivalent in the free molecule but not to an enzyme, so a single enantiomer of glycerol 3-phosphate results. Glycerol's two primary hydroxyls are prochiral, or more precisely enantiotopic: replacing one gives a different compound from replacing the other, and a chiral active site therefore treats them as distinct even though no ordinary reagent could. Oxidation of the remaining…
Building the same chain, with three deliberate differences
A pathway that builds fatty acids and one that degrades them cannot both be favorable in the same conditions if they are the same set of reactions, and a cell that ran both at once would achieve nothing but the consumption of ATP. Biosynthesis therefore performs the same four operations in reverse order, but differs from a simple reversal in every way that matters for control. The condensation is where the largest change lies. Forming the new carbon-carbon bond is a Claisen condensation, the same reaction that assembles ethyl acetoacetate from ethyl acetate in a flask. That flask reaction…
Moving an amino group, then removing it
Amino acids that are not needed for protein synthesis are broken down, and the first problem is the nitrogen. It must be removed from the carbon skeleton before that skeleton can be fed into the pathways of this chapter, and it must be removed in a controlled way, because free ammonia is toxic. The collection step is transamination, and its net effect is deceptively simple: an amino acid and an alpha-keto acid trade functional groups. Alanine and alpha-ketoglutarate give pyruvate and glutamate. No carbon-carbon bond is made or broken and there is no net oxidation, since one skeleton is…
An inventory of the chapter, by reaction type
The chapter introduces almost no new reactions. Every arrow drawn in it belongs to a family already covered - with one acknowledged omission, the lipoamide step of the pyruvate and alpha-ketoglutarate dehydrogenase complexes, where the enamine attacks a disulfide and is not drawn here - and the value of working through the pathways lies in seeing familiar chemistry operate under a constraint set that a flask never imposes: roughly neutral pH, roughly 37 degrees Celsius, water as the solvent, and millimolar concentrations. Those constraints rule out the two tools an organic chemist reaches for…
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