2.2: Vitamins as Coenzymes

Nutritional basics

Many of the metabolic enzymes discussed in this course require essential coenzymes for optimal activity. An individual's nutritional status has the potential to greatly influence their ability to efficiently oxidize fuels, and this can lead to deviations from clinical norms or illness, which would be illustrated on an individual's CMP.

It is important to be aware of the presentation of these nutritional deficiencies as they can manifest as hypoglycemia, different types of anemia, or physiological symptoms.

Overview

Vitamins are organic compounds that, for the most part, we cannot synthesize through endogenous metabolism in adequate quantities (with the exceptions of vitamins B₃, D, and K). To address these nutritional needs, we must consume vitamins as part of a balanced diet or supplement through a variety of mechanisms. Below are some key aspects of the roles vitamins play within metabolism and common symptoms associated with deficiencies (table 2.3).

Note

Water-soluble vitamins

• Water-soluble vitamins include: ascorbic acid (vitamin C), thiamin (vitamin B₁), riboflavin (vitamin B₂), niacin (vitamin B₃), pantothenic acid (vitamin B₅), pyridoxine, pyridoxal, and pyridoxamine (vitamin B₆), biotin (vitamin B₇), and cobalamin (vitamin B₁₂).
• Readily excreted in the urine, toxicity is rare.
• Deficiencies can occur quickly.
• Water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism.

Fat-soluble vitamins

• Fat-soluble vitamins include: vitamins A, D, K, and E.
• They are released, absorbed, and transported (in chylomicrons) with dietary fat.
• They are not readily excreted, and significant quantities are stored in the liver and adipose tissue.
• Most function as transcriptional regulators.
• Only one fat-soluble vitamin (vitamin K) has a coenzyme function.
• Consumption of vitamins A and D in excess of the dietary reference intakes can lead to accumulation of toxic quantities of these compounds.

Folic acid

Folic acid deficiency is a relatively common vitamin deficiency in the United States, presenting routinely as macrocytic anemia.

• Tetrahydrofolate (THF), the reduced coenzyme form of folate, receives one-carbon fragments from amino acid donors such as serine, glycine, and histidine, and transfers them to intermediates in the synthesis of amino acids, purines, and thymidine monophosphate (TMP, a pyrimidine nucleotide found in DNA).
• Inadequate serum levels of folate can be caused by increased demand (such as the case in pregnancy and lactation), inadequate dietary intake, poor absorption (caused by pathology of the small intestine), alcoholism, or treatment with drugs (for example, methotrexate).
• Folic acid supplementation before conception and during the first trimester has been shown to significantly reduce neural tube defects.

Cobalamin (vitamin B₁₂)

Vitamin B₁₂ is required in humans for two essential enzymatic reactions.

• One of the reactions is the remethylation of homocysteine to methionine, and the other involves the isomerization of methylmalonyl coenzyme A (CoA), which is produced during the degradation of some amino acids (isoleucine, valine, threonine, and methionine) and odd-chain fatty acids (FAs).
• Folic acid (as N5-methyl THF) is also required for one of the reactions needed for remethylation of homocysteine.
• Deficiency of B₁₂ or folate results in elevated Hcy levels (chapter 8), however, only a deficiency of B₁₂ will result in elevated levels of methylmalonic acid.
• Pernicious anemia is a type of vitamin B₁₂ anemia caused by a lack of intrinsic factor. Intrinsic factor (IF) is released from the parietal cells and binds vitamin B₁₂ so that it can be absorbed in the intestines.
• B₁₂ is also important in the synthesis of S-adenosylmethionine (SAM), which plays an integral role in cellular methylation reactions and neurotransmitter synthesis.

Ascorbic acid (vitamin C)

The active form of vitamin C is ascorbic acid.

• Vitamin C is used as a coenzyme in hydroxylation reactions, such as in the hydroxylation of prolyl and lysyl residues of collagen.
• It is required for the maintenance of normal connective tissue as well as for wound healing.
• Vitamin C assists in the absorption of dietary iron by reducing ferric iron to the ferrous form.

Pyridoxine (vitamin B₆)

Vitamin B₆ is a term that encompasses all derivatives of pyridine including: pyridoxine, pyridoxal, and pyridoxamine.

• Pyridoxine serves as a precursor of the biologically active coenzyme, pyridoxal phosphate (PLP).
• PLP functions as a coenzyme for activation transfer reactions, particularly those that catalyze reactions involving amino acids (section 5.3).
• Isoniazid, a drug commonly used to treat tuberculosis, can induce a vitamin B₆ deficiency by forming an inactive derivative with PLP.
• Pyridoxine is the only water-soluble vitamin with significant toxicity. Sensory neuropathies can occur at intakes exceeding five times the Tolerable Upper Limit (UL). This is defined as the maximum amount of daily vitamins and minerals that you can safely take without risk of an overdose or serious side effects.

Thiamine (vitamin B₁)

Thiamine pyrophosphate (TPP) is the biologically active form of thiamine and is generated by the transfer of a pyrophosphate group from adenosine triphosphate (ATP) to thiamine.

• TPP is a coenzyme in the formation or degradation of \(\alpha \)-ketols by transketolase (section 7.1) and in the oxidative decarboxylation of \(\alpha \)-keto acids.
• The activity of both the pyruvate dehydrogenase complex and \(\alpha \)-ketoglutarate dehydrogenase can be impaired if thiamine is deficient. This can lead to impaired production of ATP, impaired cellular function, and lactic acidosis.
• TPP is also required by branched-chain \(\alpha \)-keto acid dehydrogenase of muscle.
• Activity of erythrocyte transketolase is used to diagnosis a thiamine deficiency.
• Beriberi is a severe thiamine-deficiency syndrome found in geographic areas with poor and restricted diets.
• Wernicke-Korsakoff syndrome can present in individuals with alcohol abuse disorder. Common symptoms include confusion, ataxia, and nystagmus.

Niacin (vitamin B₃)

Niacin, or nicotinic acid, is a substituted pyridine derivative. The biologically active coenzyme forms are nicotinamide adenine dinucleotide (NAD\(^+\)) and its phosphorylated derivative, nicotinamide adenine dinucleotide phosphate (NADP\(^+\)).

• Nicotinamide is readily deaminated in the body and, therefore, is nutritionally equivalent to nicotinic acid.
• NAD\(^+\) and NADP\(^+\) serve as coenzymes in oxidation-reduction reactions in which the coenzyme undergoes reduction of the pyridine ring by accepting a hydride ion.
• A deficiency of niacin causes pellagra, which encompasses the three Ds: dermatitis, diarrhea, and dementia.
• Hartnup disorder, characterized by defective absorption of tryptophan, can result in pellagra-like symptoms.

Riboflavin (vitamin B₂)

The two biologically active forms of B₂ are flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), formed by the transfer of an adenosine monophosphate moiety from ATP to FMN.

• FMN and FAD are each capable of reversibly accepting two hydrogen atoms, forming FMNH\(_2\) or FADH\(_2\). FMN and FAD are bound tightly, or covalently, to flavoenzymes that catalyze the oxidation or reduction of a substrate.
• Riboflavin deficiency is not associated with a major human disease, although it frequently accompanies other vitamin deficiencies.

Biotin (vitamin B₇)

Biotin is a coenzyme in carboxylation reactions, in which it serves as a carrier of activated carbon dioxide (coenzyme for acetylCoA carboxylase and pyruvate carboxylase).

• Biotin is covalently bound to the \(\varepsilon \)-amino group of lysine residues in biotin-dependent enzymes.
• Biotin deficiency does not occur naturally because the vitamin is widely distributed in food.
• Excessive consumption of raw egg white as a source of protein can cause symptoms of biotin deficiency. Symptoms may include: dermatitis, glossitis, loss of appetite, and nausea. Raw egg white contains avidin, which is a glycoprotein that tightly binds biotin and prevents its absorption from the intestine.

Pantothenic acid

Pantothenic acid is a component of CoA, which functions in the transfer of acyl groups.

• CoA contains a thiol group that carries acyl compounds as activated thiol esters. Examples of such structures are succinyl-CoA, fatty acyl-CoA, and acetyl-CoA.
• Pantothenic acid is also a component of the acyl carrier protein domain of fatty acid synthase (section 4.4).
• The vitamin is widely distributed in a variety of foods, and deficiency is not well characterized in humans.

Vitamin A

The retinoids are a family of molecules that are related to dietary retinol (vitamin A).

• Vitamin A (and its metabolites) are important for vision, reproduction, growth, immune function, and maintenance of epithelial tissues.
• Retinoic acid is derived from the oxidation of retinol and mediates most of the actions of the retinoids. 
• Retinol is oxidized to retinoic acid. Retinoic acid binds specifically to a family of nuclear receptors (retinoic acid receptors, RAR) and modulates gene expression in target tissues, such as epithelial cells. The activated retinoic acid‒RAR complex binds to response elements on DNA and recruits activators or repressors to regulate retinoid-specific mRNA synthesis (figure 2.3).

Figure 2.3: Mechanism of action of vitamin A.

Vitamin D

The D vitamins are a group of sterols that have a hormone-like function.

• The active molecule, 1,25-dihydroxycholecalciferol (calcitriol), binds to intracellular receptor proteins. The receptor complex interacts with DNA in the nucleus of target cells in a manner similar to that of vitamin A and either selectively stimulates or represses gene transcription.
• The most prominent actions of calcitriol are to regulate the plasma levels of calcium and phosphorus. Within the gastrointestinal tract, calcitriol increases the transcription of calcium transport proteins, calbindin-D proteins, which results in increased uptake of calcium. It also increases reabsorption of phosphorus through a similar mechanism.

Vitamin K

• The primary role of vitamin K is to serve as a coenzyme in the carboxylation of glutamic acid residues; this post-translational modification is required for the functioning of many proteins required for blood clotting.
• Vitamin K is required in the hepatic synthesis of prothrombin (factor II) and factors VII, IX, and X (figure 2.4).

Figure 2.4: Vitamin K stimulates the maturation of clotting factors.

• The formation of carboxy-glutamyl (Gla) residues is sensitive to inhibition by warfarin, an analog of vitamin K that inhibits vitamin K epoxide reductase (VKOR), the enzyme required to regenerate the functional hydroquinone form of vitamin K.

Vitamin E

The E vitamins consist of eight naturally occurring tocopherols, of which \(\alpha\)-tocopherol is the most active.

• The primary function of vitamin E is as an antioxidant in prevention of the nonenzymatic oxidation of cell components.
• Vitamin E deficiency in adults is usually associated with defective lipid absorption or transport.

Table 2.3: Summary table of vitamins.

Vitamin	Other names	Active form	Function	Deficiency	Signs and symptoms	Toxicity	Notes
Water soluble
Vitamin B9	Folic acid	Tetrahydrofolic acid	Transfer one-carbon units; synthesis of methionine, purines, and thymidine mono-phosphate	Megaloblastic anemia Neural tube defects	Anemia Birth defects	None	Administration of high levels of folate can mask vitamin B12 deficiency
Vitamin B12	Cobalamin	Methylcobalamin Deoxyadenosyl cobalamin	Coenzyme for reactions: homocysteine → methionine methylmalonyl-CoA → succinyl-CoA	Pernicious anemia Dementia Spinal degeneration	Megaloblastic anemia Neuropsychiatric symptoms	None	Pernicious anemia is treated with intramuscular or high-dose oral vitamin B12
Vitamin C	Ascorbic acid	Ascorbic acid	Antioxidant Coenzyme for hydroxylation reactions, for example in procollagen: proline → hydroxyproline lysine → hydroxylysine	Scurvy	Sore, spongy gums Loose teeth Poor wound healing	None	Benefits of supplementation not established in controlled trials
Vitamin B6	Pridoxine Pyridoxamine Pyridoxal	Pyridoxal phosphate	Coenzyme for enzymes, particularly in amino acid metabolism	Rare	Glossitis Neuropathy	Yes	Deficiency can be induced by isoniazid Sensory neuropathy occurs at high doses
Vitamin B1	Thiamine	Thiamine pyrophosphate	Coenzyme of enzymes catalyzing: pyruvate → acetyl-CoA α-Ketoglutarate → succinyl-CoA Ribose 5-P + xylulose 5-P → Sedoheptulose 7-P + Glyceraldehyde 3-P Branched-chain α-keto acid oxidation	Beriberi Wernicke-Korsakoff syndrome (most commin in alcoholics)	Tachycardia, vomiting, convulsions Apathy, loss of memory, dysregulated eye movements	None
Niacin	Nicotinic acid Nicotinamide	NAD^+ NADP^+	Electron transfer	Pellagra	Dermatitis Diarrhea Dementia	None	High doses of niacin used to treat hyperlipidemia
Vitamin B2	Riboflavin	FMN FAD	Electron transfer	Rare	Dermatitis Angular stomatitis	None
Biotin		Enzyme-bound biotin	Carboxylation reactions	Rare		None	Consumption of large amounts of raw egg whites (which contain a protein, avidin, that binds biotin) can induce a biotin deficiency
Pantothenic acid		Coenzyme A	Acyl carrier	Rare		None
Fat soluble
Vitamin A	Retinol Retinal Retinoic acid ß-Carotene	Retinol Retinal Retinoic acid	Maintenance of reproduction Vision Promotion of growth Differentiation and maintenance of epithelial tissues Gene expression	Infertility Night blindness Retardation of growth Xerophthalmia	Increased visual threshold Dryness of cornea	Yes	ß-Carotene not acutely toxic, but supplementation is not recommended Excess vitamin A can increase incidence of fractures
Vitamin D	Cholecalciferol Ergocalciferol	1,25-dihydroxy-cholecalciferol	Calcium uptake Gene expression	Rickets (in children) Osteomalacia (in adults)	Soft, pliable bones	Yes	Vitamin D is not a true vitamin because it can be synthesized in skin; application of sunscreen lotions or presence of dark skin color decreases this synthesis
Vitamin K	Menadione Menaquinone Phylloquinone	Menadione Menaquinone Phylloquinone	Gamma Carboxylation of glutamate residues in clotting and other proteins	Newborn Rare in adults	Bleeding	Rare	Vitamin K produced by intestinal bacteria Vitamin K deficiency common in newborns Intramuscular treatment with vitamin K is recommended at birth
Vitamin E	α-Tocopherol	Any of several tocopherol derivatives	Antioxidant	Rare	Red blood cell fragility leads to hemolytic anemia	None	Benefits of supplementation not established in controlled trials

 

References and resources

Text

Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017, Chapter 27: Nutrition: Overview, Chapter 28: Micronutrients: Vitamins, Chapter 29: Micronutrients: Minerals.

Le, T., and V. Bhushan. First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 65–71.

Figures

Ferrier D. Figure 2.3 Mechanism of action of Vitamin A. Adapted under Fair Use from Figure 28.20 Action of the retinoids. Lippincott Illustrated Reviews Biochemistry. 7th Ed. pp388. 2017. Chemical structure by Henry Jakubowski.

Grey, Kindred, Figure 2.4 Vitamin K stimulates the maturation of clotting factors. 2021. Chemical structure by Henry Jakubowski. https://archive.org/details/2.6_20210924. CC BY 4.0.

Tables

Table 2.3 adapted from Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017.