Preface

The chemical biology of carbon can be recast as the organic chemistry of life. The rules of functional group reactivity, electronics, and stereochemistry that govern abiotic organic chemistry are carried over without exception to the organic chemical transformations, metabolism, that occur in living organisms. Readers with only one to two semesters of organic chemistry background will readily navigate familiar concepts to analyze the organic chemistry of life. Yet, this approach to carbon chemical biology should also be instructive to graduate and postgraduate students, medicinal chemists, organic chemists, and chemical biologists in industry and academic research settings.

There is an underlying chemical and molecular logic that organisms, including humans, employ to interconvert hundreds of thousands of organic reactants onto products. That dynamic organic chemical inventory is bent to two major metabolic purposes. One is to extract energy from dietary intake into chemically useful molecules. The second purpose is to use those molecules, a core group of thermodynamically active but kinetically stable molecules, for all the biosynthetic pathways that sustain growth, enable information storage, and transfer in biopolymers such as DNA, RNA, and proteins.

We approach the complexities of the organic chemistry of life in Section II from a few principles of molecular structure and reactivity that govern abiotic organic chemistry. A first theme, encompassing Section II, Chapters 2–5, is to analyze the major classes of organic metabolites according to their functional groups since those condition possible reactivities.

These start with the simplest functional group, alkene formation and reactivity, then proceed to C–O hetero functional groups (e.g. alcohols, aldehydes, acids, carbon dioxide), C–S functional groups (thiols, thioethers, thioesters, disulfides), and C–N functional groups (amines, imines, amides). Because the five elements C, H, O, N, and S make up 98% of the mass of human bodies, this approach catalogs essentially all the common functional group chemistry available to carbon in biologic systems. Carbon–sulfur chemistry in particular, not usually taught in introductory organic chemistry, is uniquely placed in life's chemical firmament. So is phosphate ester and phosphate anhydride chemical biology.

A second theme is oxidation–reduction chemistry that relates most of the inventory of organic metabolite functional groups to each other. Alkane to alcohol, alcohol to aldehyde or ketone, aldehyde to acid and acid to one carbon shorter alkane and CO₂, amine to imine to amide, dithiol to disulfide are all related by net two electron transfer steps. This lens is not only useful for understanding the flow of organic substrates through metabolic pathways. It also illuminates the chemical logic for such energy-yielding pathways as glycolysis, fatty acid oxidations and the citric acid cycle. This integrated redox and functional group-centered approach similarly demystifies the chemical steps and strategies in fatty acid biosynthesis and all the many variations of isoprenoid and steroid assemblies.

A third principle that enables prediction of the reactivity of the great bulk of organic metabolites is the chemical principle of nucleophilicity (the reaction of electron rich functional groups) and its opposite, electrophilicity (the reaction behavior of electron poor functional groups). All C–C bonds made or broken in vivo in two electron reaction manifolds are explicable by nucleophiles capturing electrophiles.

Section III of this book works off another central premise: that nature has espoused heterocycles. Nature apparently needs rigid, constrained molecular structures in general, introducing regio- and stereocontrol for high affinity interactions with biologic targets (enzymes, receptors, RNA, DNA). Chapters 6–9 start with a chapter devoted to purines and pyrimidines, nitrogen-containing heterocyclic building blocks for RNA and DNA that may have been among the earliest heterocycles to emerge during molecular evolution. Chapter 7 summarizes major classes of natural carbacycles, from three to eight carbons, examining assembly principles. These include the assembly logic for bioconstruction of single and fused aromatic ring systems.

Chapters 8 and 9 examine two other aspects of nitrogen heterocycles. The first deals with additional metabolically central low molecular weight nitrogen metabolites including, pyrrole rings, the pyrrolidine ring of proline, the 1,3-bis nitrogen imidazole side chain of histidine and the bicyclic indole ring of tryptophan. How they form and how they react are key features of biological catalysis. Chapter 9 turns to the vitamin heterocycles noting that 9 of 13 human vitamins function as chemo-specific coenzymes to use their distinct heterocycles to enable life-sustaining human chemistry.

Among the array of nitrogen heterocycles brought to bear are the thiazolium ring of thiamin, the pyridinium ring of nicotinamides, the tricyclic isoalloxazine ring system of riboflavin, the pyridine aldehyde coenzyme form of pyridoxal-phosphate, the bicyclic pterin ring of tetrahydrofolate coenzymes, and an oxygen heterocycle, the radical scavenging cyclic enediolate ring of vitamin C. Nature has conscripted a chemical menagerie of heterocycles essential for the reactions of life where the chemistry accessible to each different heterocycle has been evolved to fit essential biologic function.

From these fundamental precepts of chemical reactivity and the inventory of organic functional groups in nature, we turn in Section IV, Chapters 10–13, to the very few types of reactions that organic molecules can undergo in living organisms. The reactions of carbon functional groups in biologic systems are essentially limited to four mechanistic manifolds.

One can exemplify the possibilities for a substrate which undergoes a C–H bond cleavage in the active site of an enzyme catalyst. The C–H bond can only break heterolytically or homolytically. Two heterolytic possibilities exist: the electrons in the bond, as it breaks, stay with the carbon (an incipient carbanion) as the hydrogen departs as a proton (H⁺). At the other extreme, the two electrons depart with the hydrogen as a hydride ion (H⁻), leaving an incipient electron deficient carbocation atom. There is only one homolytic (equal-breaking) C–H bond cleavage outcome. One electron remains with carbon as an incipient carbon radical while one electron departs with the hydrogen as a hydrogen atom (H˙).

The two heterolytic and one homolytic routes then generate three types of carbon-centered transition states, or, if they have finite lifetimes beyond the 10⁻¹³ s⁻¹ half life of a molecular vibration, yield carbon-centered unstable intermediates. Proton transfers yield carbanions. Hydride transfers yield carbocations. Hydrogen atom transfers yield carbon radicals. These are the three possible carbon-centered intermediates in reactions, whether in abiotic organic chemistry or the organic chemistry of life. (Carbenoid pathways are not generally operant.)

The fourth reaction mode possibility is the lack of any reaction intermediates, with a smooth energy surface between reactant(s) and product(s). In abiotic chemistry these are concerted, pericyclic reactions, collated in the 1960s by the Woodward Hoffmann rules that explained allowed reactions pathway based on orbital symmetry principles. In the past two decades a variety of biological pericyclic reactions have been discovered and validated, bringing into view diverse families of pericyclase enzymes that catalyze four types of possible cyclic reaction manifolds in carbon chemical biology.

Section V, the concluding section, consists of Chapters 14–16. They examine three distinct iconic organic metabolites, the polyhydroxy-aldehyde glucose, the linear hexa-olefinic hydrocarbon squalene, and the aminomethylpyrrole nitrogen heterocycle porphobilinogen. Each metabolite is examined in the context of metabolic pathways where key chemical steps utilize the specific functional groups available to those substrates.

Glucose, as equilibrating linear aldehyde with its predominant cyclic hemiacetal forms, reveals the diversity of carbonyl and redox chemistry in three pathways: glycolysis, the pentose-phosphate pathway, and polysaccharide chain elongations (Chapter 14).

Squalene is a key isoprenoid C₃₀ hydrocarbon built from head to tail five carbon alkylations and then a head to head self-alkylation of two C₁₅ units, before undergoing directed cyclization cascades to the tetra- and pentacyclic frameworks of sterols (Chapter 15).

Finally, Chapter 16 focuses on the pyrrolic nitrogen heterocyclic porphobilinogen. Its chemical capacity to serve as precursor to both carbon nucleophile and carbon electrophile is the underlying chemical tenet to tetrapyrrole macrocycle biosynthetic logic. Prophobilinogen's pyrrole ring-based chemical versatility to form C–C bonds in linear tetrapyrroles and then undergo directed cyclization to the tetrapyrrole macrocycle framework is the key assembly principle for the pigments of life.

These few organic chemical principles anchor the organic chemistry of life. They deconvolute the complexities of metabolite dynamics, illuminate metabolic pathways that intersect at certain nodal points, and address issues of carbon economy. The principles explain control of reactivity of such promiscuous molecules as NH₃, H₂S, CH₂ = O, validate the value of a few core C = C, C–O, C–S, and C–N functional groups among the myriad organic metabolites, and detail the life giving chemical features of heterocyclic metabolites and coenzymes. This approach to the chemical biology of carbon uncovers and illustrates the underlying chemical logic for major pathways that utilize the rules and constraints of abiotic organic chemistry in the organic chemistry of life. The chemical biology of carbon subsumes much of the chemical biology of hydrogen and oxygen, and integrates and builds on the chemical biology of sulfur, nitrogen, and phosphorus. Together, these six elements account for 99% of the mass of the human body.

Christopher T. Walsh