Chapter 2: The Chemical Logic for Major Reaction Types

This chapter defines a core set of central metabolites that are thermodynamically activated but sufficiently stable kinetically to serve as diffusible molecules that power coupled reaction equilibria to drive biosynthesis in both primary and secondary pathways. Three such molecules are adenosine triphosphate (ATP), acetyl-coenzyme A (CoA), and the reduced nicotinamide coenzymes NADH and NADPH, which serve as cellular currencies for phosphoryl-, acetyl-, and electron transfers, respectively. ATP's thermodynamic activation arises from its kinetically stable side chain phosphoric anhydride linkages; acetyl-CoA from its acyl thioester grouping, and NAD(P)H from the dihydropyridinium ion linkage. S-Adenosylmethionine, with its activated sulfonium cation group, can transfer methyl, aminobutyryl, and adenosyl groups to cosubstrates as electrophilic or as radical fragments. Carbamoyl phosphate is a biologic carbamoylating reagent due to its mixed acyl phosphoric anhydride core. UDP-glucose and congeneric NDP-hexoses are fragmentable enzymatically into C₁-glucosyl electrophiles for capture by cosubstrate nucleophiles. The delta 2- and 3-double bonds in isopentenyl-PP isomers serve as electrophilic and nucleophilic partners, respectively, for C–C bond-forming alkylations at the start of all isoprenoid biosynthetic pathways. Adenosine-5′-phosphosulfate is activated for sulfuryl group transfer via its mixed sulfuric-phosphoric acid side chain linkage. Molecular oxygen (O₂) is kinetically stable enough to comprise 21% of Earth's atmosphere, but is thermodynamically activated to be the terminal electron acceptor in aerobic metabolism. Its controlled reductive cleavage is the driving force for introduction of diverse oxygen functional groups in a plethora of natural product maturations.