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2.2: Vitamins as Coenzymes

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    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.


    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).


    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).

    The target cell cytosol is a large circle and contains the nucleus as a small circle. Plasma retinol or (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcylcohexen-1-yl)nona-2,4,6,8-tetraen-1-ol is shown outside of the cell and transitions to retinol and then retinoic acid within the cytosol of the target cell. There is a text box after retinoic acid that states “Retinol is oxidized to retinoic acid. Movement from cytosol to nucleus is guided by cellular retinol-binding proteins and cellular retinoic acid-binding proteins''. Then retinoic acid or (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcylochexen-1-yl)nona-2,4,6,8-tetraenoic acid is shown in the nucleus and combines with the inactive receptor to form the activated receptor complex, to gene, to mRNA. There is a text box pointing to the activated receptor complex that states “Retinoic acid binds to the intranuclear receptor”. There is a textbox pointing to the gene that states “Retinoic acid receptor complex binds to chromatin, activating the transcription of specific genes”. The mRNA moves into the cytosol and transitions to specific proteins to cellular differentiation.

    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).
    Glutamyl residue with a polypeptide to the left and precursors of clotting factors II, VII, IX, X to the right. Arrow with enzyme γ-glutamyl carboxylase and addition of O2 and CO2 to γ-carboxyglutamyl (Gla) residue with a polypeptide to the left and mature clotting factors II, VII, IX, X to the right. Vitamin K activates and warfarin inhibits the reaction. 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


    Birth defects

    None Administration of high levels of folate can mask vitamin B12 deficiency
    Vitamin B12 Cobalamin


    Deoxyadenosyl cobalamin

    Coenzyme for reactions:

    • homocysteine → methionine
    • methylmalonyl-CoA → succinyl-CoA

    Pernicious anemia


    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


    Coenzyme for hydroxylation reactions, for example in procollagen:

    • proline → hydroxyproline
    • lysine → hydroxylysine

    Sore, spongy gums

    Loose teeth

    Poor wound healing

    None Benefits of supplementation not established in controlled trials
    Vitamin B6




    Pyridoxal phosphate Coenzyme for enzymes, particularly in amino acid metabolism Rare




    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


    Wernicke-Korsakoff syndrome (most commin in alcoholics)

    Tachycardia, vomiting, convulsions

    Apathy, loss of memory, dysregulated eye movements


    Nicotinic acid




    Electron transfer Pellagra




    None High doses of niacin used to treat hyperlipidemia
    Vitamin B2 Riboflavin



    Electron transfer Rare


    Angular stomatitis

    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



    Retinoic acid




    Retinoic acid

    Maintenance of reproduction


    Promotion of growth

    Differentiation and maintenance of epithelial tissues

    Gene expression


    Night blindness

    Retardation of growth


    Increased visual threshold

    Dryness of cornea


    ß-Carotene not acutely toxic, but supplementation is not recommended

    Excess vitamin A can increase incidence of fractures

    Vitamin D




    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







    Gamma Carboxylation of glutamate residues in clotting and other proteins


    Rare in adults



    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


    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.


    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. CC BY 4.0.


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

    This page titled 2.2: Vitamins as Coenzymes is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Renee J. LeClair (Virginia Tech Libraries' Open Education Initiative) .