The Organic Chemistry Of Biological Pathways Pdf
The organic chemistry of biological pathways
The organic chemistry of biological pathways is a branch of biochemistry that studies the molecular mechanisms and structures of the chemical reactions that occur in living organisms. It aims to bridge the gap between biochemistry and mechanistic organic chemistry, and to understand how biomolecules are synthesized, degraded, and regulated in various metabolic pathways.
In this article, we will review some of the key concepts and examples of the organic chemistry of biological pathways, based on the book by John McMurry and Tadhg Begley. We will also provide some links to online resources where you can access more information and download the structures of enzymes and metabolites involved in these pathways.
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Common mechanisms in biological chemistry
The first chapter of the book introduces some of the common reaction mechanisms that are found in biological chemistry, such as nucleophilic substitutions, eliminations, additions, oxidations, reductions, rearrangements, and radical reactions. It also explains how enzymes catalyze these reactions by providing specific binding sites, stabilizing transition states, and facilitating proton transfers. Some examples of these mechanisms are:
The SN2 reaction of thiamine pyrophosphate (TPP) with pyruvate to form hydroxyethyl-TPP, which is a key step in the pyruvate dehydrogenase complex that converts pyruvate to acetyl-CoA.
The E1cb elimination of water from hydroxyethyl-TPP to form acetyl-TPP, which is followed by a nucleophilic attack of CoA to form acetyl-CoA and regenerate TPP.
The addition of water to fumarate to form malate, which is catalyzed by fumarase in the citric acid cycle. The enzyme uses a histidine residue to abstract a proton from water and form an enolate intermediate, which then attacks the double bond of fumarate.
The oxidation of malate to oxaloacetate by malate dehydrogenase, which involves a hydride transfer from malate to NAD+ to form NADH and a carbanion intermediate, which then accepts a proton from water to form oxaloacetate.
The rearrangement of chorismate to prephenate, which is catalyzed by chorismate mutase in the biosynthesis of aromatic amino acids. The enzyme uses a glutamate residue to stabilize the negative charge on the carbon atom that migrates from one ring to another.
The radical reaction of ribonucleotide reductase, which converts ribonucleotides to deoxyribonucleotides for DNA synthesis. The enzyme uses a tyrosyl radical to abstract a hydrogen atom from the 3'-hydroxyl group of the ribose ring, forming a 3'-radical intermediate, which then eliminates a hydroxyl radical to form a deoxyribose ring.
Biomolecules
The second chapter of the book gives an overview of the structures and functions of the major classes of biomolecules, such as carbohydrates, lipids, amino acids, proteins, nucleotides, and nucleic acids. It also discusses the chirality and stereochemistry of these molecules, and how they are determined by their biosynthesis and degradation pathways. Some examples of these biomolecules are:
Carbohydrates are polyhydroxy aldehydes or ketones that can exist as linear or cyclic forms. They can be classified into monosaccharides (such as glucose and fructose), disaccharides (such as sucrose and lactose), oligosaccharides (such as maltose and cellobiose), and polysaccharides (such as starch and cellulose). Carbohydrates serve as energy sources, structural components, and signaling molecules in living organisms.
Lipids are hydrophobic molecules that can be classified into fatty acids (such as palmitic acid and oleic acid), triacylglycerols (such as tristearin and triolein), phospholipids (such as phosphatidylcholine and phosphatidylserine), glycolipids (such as cerebrosides and gangliosides), steroids (such as cholesterol and testosterone), and terpenes (such as geranyl pyrophosphate and squalene). Lipids serve as energy storage, membrane components, hormones, and vitamins in living organisms.
Amino acids are molecules that contain an amino group and a carboxylic acid group attached to a central carbon atom, which also bears a variable side chain. There are 20 common amino acids that are encoded by the genetic code, and they can be classified into nonpolar, polar, acidic, and basic groups. Amino acids are the building blocks of proteins, which are linear polymers of amino acids linked by peptide bonds. Proteins serve as enzymes, structural components, transporters, receptors, antibodies, and hormones in living organisms.
Nucleotides are molecules that consist of a nitrogenous base (such as adenine and guanine), a pentose sugar (such as ribose and deoxyribose), and one or more phosphate groups. Nucleotides serve as energy carriers (such as ATP and GTP), cofactors (such as NAD+ and FAD), and signaling molecules (such as cAMP and cGMP) in living organisms. Nucleic acids are linear polymers of nucleotides linked by phosphodiester bonds. There are two types of nucleic acids: DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). DNA stores the genetic information that is inherited from one generation to another, while RNA mediates the expression of this information into proteins.
Lipid metabolism
The third chapter of the book describes the metabolic pathways of lipids, such as the oxidation of fatty acids, the synthesis of fatty acids, the degradation of triacylglycerols, the synthesis of triacylglycerols, the metabolism of ketone bodies, the biosynthesis of cholesterol, the biosynthesis of bile acids, and the biosynthesis of steroid hormones. Some examples of these pathways are:
The oxidation of fatty acids is the process of breaking down fatty acids into acetyl-CoA units that can enter the citric acid cycle for energy production. The oxidation occurs in the mitochondria and involves four steps: dehydrogenation by acyl-CoA dehydrogenase, hydration by enoyl-CoA hydratase, dehydrogenation by 3-hydroxyacyl-CoA dehydrogenase, and thiolytic cleavage by acyl-CoA acetyltransferase. Each cycle produces one molecule of FADH2, one molecule of NADH, and one molecule of acetyl-CoA.
The synthesis of fatty acids is the process of building up fatty acids from acetyl-CoA units that are derived from carbohydrates or amino acids. The synthesis occurs in the cytoplasm and involves four steps: carboxylation by acetyl-CoA carboxylase, condensation by malonyl-CoA:ACP transacylase and 3-ketoacyl-ACP synthase, reduction by 3-ketoacyl-ACP reductase, dehydration by 3-hydroxyacyl-ACP dehydratase, and reduction by enoyl-ACP reductase. Each cycle consumes one molecule of ATP, two molecules of NADPH, and one molecule of malonyl-CoA.
The degradation of triacylglycerols is the process of releasing fatty acids from triacylglycerols that are stored in adipose tissue. The degradation is stimulated by hormones such as glucagon and epinephrine, which activate hormone-sensitive lipase. This enzyme hydrolyzes the ester bonds between the fatty acids and glycerol in triacylglycerols, releasing free fatty acids and glycerol into the bloodstream. The free fatty acids can then be transported to other tissues for oxidation or synthesis, while glycerol can be converted to glucose in the liver.
The synthesis of triacylglycerols is the process of esterifying fatty acids with glycerol to form triacylglycerols that can be stored in adipose tissue. The synthesis occurs mainly in the liver and involves three steps: phosphorylation of glycerol by glycerol kinase, acylation of glycerol-3-phosphate by glycerol-3-phosphate acyltransferase and 1-acylglycerol-3-phosphate acyltransferase, and dephosphorylation of phosphatidate by phosphatidate phosphatase. The fatty acids used for the synthesis can be derived from dietary sources or endogenous sources.
The metabolism of ketone bodies is the process of producing or utilizing ketone bodies (such as acetoacetate, 3-hydroxybutyrate, and acetone) as alternative fuel sources when glucose is scarce. The production occurs mainly in the liver during fasting or diabetes mellitus, when excess acetyl-CoA from fatty acid oxidation cannot enter the citric acid cycle, and instead condense to form acetoacetyl-CoA, which then cleaves to form acetoacetate. Acetoacetate can be reduced to 3-hydroxybutyrate by 3-hydroxybutyrate dehydrogenase, or decarboxylated to acetone by acetoacetate decarboxylase. The utilization occurs mainly in the brain, heart, and skeletal muscle during prolonged fasting or starvation, when ketone bodies can cross the blood-brain barrier and be converted back to acetyl-CoA by 3-ketoacyl-CoA transferase and thiolase.
The biosynthesis of cholesterol is the process of synthesizing cholesterol from acetyl-CoA units. The biosynthesis occurs mainly in the liver and involves four stages: the formation of mevalonate from three molecules of acetyl-CoA by acetoacetyl-CoA thiolase, HMG-CoA synthase, and HMG-CoA reductase; the conversion of mevalonate to isopentenyl pyrophosphate by mevalonate kinase, phosphomevalonate kinase, and mevalonate diphosphate decarboxylase; the polymerization of isopentenyl pyrophosphate to squalene by isopentenyl pyrophosphate isomerase, geranyl pyrophosphate synthase, farnesyl pyrophosphate synthase, and squalene synthase; and the cyclization of squalene to cholesterol by squalene monooxygenase and lanosterol synthase. Cholesterol serves as a precursor for bile acids, steroid hormones, and vitamin D in living organisms.
The biosynthesis of bile acids is the process of converting cholesterol to bile acids (