Important Coenzymes

Why This Matters

Coenzymes are the unsung heroes of metabolism—without them, enzymes would sit idle and your cells couldn't extract energy from food, build new molecules, or even replicate DNA. In biochemistry, you're being tested on more than just names and structures; you need to understand how coenzymes participate in reactions, whether they're carrying electrons, acyl groups, or one-carbon units. These molecules connect the major metabolic pathways you'll encounter repeatedly: glycolysis, the citric acid cycle, oxidative phosphorylation, and biosynthesis.

The key to mastering coenzymes is recognizing their functional categories. Some are electron carriers that shuttle reducing equivalents to the electron transport chain. Others are group transfer coenzymes that activate and move chemical groups between molecules. Still others specialize in one-carbon metabolism, essential for nucleotide synthesis and methylation reactions. Don't just memorize structures—know what each coenzyme carries and which pathways depend on it.

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Electron Carriers in Energy Metabolism

These coenzymes accept and donate electrons during redox reactions, linking catabolic pathways to ATP production. They exist in oxidized and reduced forms, with the reduced forms carrying high-energy electrons to the electron transport chain.

Nicotinamide Adenine Dinucleotide (NAD⁺/NADH)

• Primary electron carrier in catabolism—accepts two electrons and one proton to form NADH, which delivers electrons to Complex I of the electron transport chain
• Oxidized form (NAD⁺) acts as the electron acceptor in glycolysis, pyruvate oxidation, and the citric acid cycle
• Each NADH yields ~2.5 ATP during oxidative phosphorylation, making it central to cellular energy production

Flavin Adenine Dinucleotide (FAD/FADH₂)

• Tightly bound cofactor in dehydrogenase enzymes—unlike NAD⁺, FAD typically remains attached to its enzyme (as a prosthetic group)
• Accepts two electrons and two protons to form FADH₂, which enters the electron transport chain at Complex II
• Each FADH₂ yields ~1.5 ATP—less than NADH because it bypasses Complex I and its proton-pumping capacity

Nicotinamide Adenine Dinucleotide Phosphate (NADP⁺/NADPH)

• Dedicated to anabolic reactions—provides reducing power for biosynthesis rather than ATP production
• Generated primarily in the pentose phosphate pathway, where glucose-6-phosphate dehydrogenase produces NADPH
• Essential for fatty acid synthesis, cholesterol synthesis, and maintaining reduced glutathione for antioxidant defense

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Acyl Group Transfer Coenzymes

These coenzymes activate and carry acyl groups (especially acetyl and other fatty acyl units), enabling their transfer between molecules. The thioester bond they form is high-energy, making the attached group chemically reactive.

Coenzyme A (CoA)

• Carries acyl groups via a reactive thiol (-SH) group—acetyl-CoA is the most famous example, linking glycolysis to the citric acid cycle
• Central metabolic hub connecting carbohydrate, fat, and protein metabolism through acetyl-CoA formation
• Required for fatty acid oxidation and synthesis, as well as cholesterol and ketone body production

Lipoic Acid

• Covalently attached cofactor in multienzyme complexes—functions in pyruvate dehydrogenase and α-ketoglutarate dehydrogenase
• Contains a disulfide bond that undergoes reversible reduction, allowing it to accept and transfer acyl groups to CoA
• Also functions as an antioxidant, regenerating vitamins C and E in their reduced forms

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Decarboxylation and Keto Acid Metabolism

These coenzymes assist in removing carboxyl groups (as $CO_2$) from substrates, a critical step in energy metabolism. They're essential for processing pyruvate and α-ketoglutarate in central metabolic pathways.

Thiamine Pyrophosphate (TPP)

• Active form of vitamin B1 (thiamine)—deficiency causes beriberi and Wernicke-Korsakoff syndrome
• Essential for α-keto acid decarboxylation in pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase
• Contains a thiazolium ring that stabilizes carbanion intermediates during catalysis

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Amino Acid Metabolism Coenzymes

These coenzymes facilitate the interconversion, synthesis, and breakdown of amino acids. They're particularly important for transamination reactions that redistribute nitrogen among carbon skeletons.

Pyridoxal Phosphate (PLP)

• Active form of vitamin B6—required by over 140 enzymes, more than any other coenzyme
• Forms a Schiff base with amino acid substrates, enabling transamination, decarboxylation, and racemization reactions
• Essential for neurotransmitter synthesis—required for producing serotonin, dopamine, GABA, and histamine

Biotin

• Carries activated $CO_2$ (as carboxybiotin)—covalently attached to carboxylase enzymes via a lysine residue
• Essential for gluconeogenesis through pyruvate carboxylase, which converts pyruvate to oxaloacetate
• Required for fatty acid synthesis via acetyl-CoA carboxylase, the committed step in the pathway

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One-Carbon Metabolism

These coenzymes carry and transfer single-carbon units at various oxidation states, essential for nucleotide biosynthesis and methylation reactions. Deficiencies in this pathway have serious consequences for rapidly dividing cells.

Tetrahydrofolate (THF)

• Carries one-carbon units at oxidation states ranging from methyl ($-CH_3$) to formyl ($-CHO$)
• Essential for purine and thymidine synthesis—explains why folate deficiency causes megaloblastic anemia and neural tube defects
• Works with vitamin B12 in the methionine synthase reaction, linking folate and B12 metabolism

Cobalamin (Vitamin B12)

• Contains a cobalt ion coordinated in a corrin ring—the only vitamin with a metal-carbon bond
• Required for methionine synthase, which regenerates methionine from homocysteine and transfers methyl groups from THF
• Essential for methylmalonyl-CoA mutase—deficiency causes methylmalonic aciduria and neurological damage

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Quick Reference Table

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Self-Check Questions

1. Which two coenzymes both carry electrons but serve opposite metabolic purposes (catabolism vs. anabolism)?

2. In the pyruvate dehydrogenase complex, what is the sequence of coenzyme involvement, and what does each contribute to the overall reaction?

3. Compare and contrast how PLP and biotin participate in amino acid metabolism—what types of reactions does each facilitate?

4. A patient with vitamin B12 deficiency develops folate deficiency symptoms even with adequate folate intake. Explain this "methyl trap" phenomenon using your knowledge of one-carbon metabolism.

5. Which coenzymes would be affected by deficiencies in vitamins B1, B6, and B12, and what metabolic pathways would be impaired in each case?