Water Soluble Vitamins

Overview

• Examples
  • B₁ (thiamine: TPP)
  • B₂ (riboflavin: FAD and FMN)
  • B₃ (niacin: NAD+)
  • B₅ (pantothenic acid: CoA)
  • B₆ (pyridoxine: PLP)
  • B₁₂ (cobalamin)
  • C (ascorbic acid)
  • biotin
  • folate
• Characteristics
  • when consumed in excess are eliminated in the urine
    • exceptions are B₁₂ and folate (stored in liver)
• B-complex deficiencies often result in dermatitis, glossitis, diarrhea

Vitamin B₁ (Thiamine)Function

a cofactor for several enzymes such as thiamine pyrophosphate (TPP) 

pyruvate dehydrogenase (glycolysis)

α-ketoglutarate dehydrogenase (TCA cycle)

transketolase (HMP shunt)

branched-chain AA dehydrogenase (metabolism of Val, Leu, Ile)

Deficiency 

causes

alcoholism

most common cause in US

EtOH interferes with thiamine absorption in small intestine

malnutrition

non-enriched rice

symptoms

impaired glucose breakdown due to decreased activity of pyruvate dehydrogenase

leads to ATP depletion

highly aerobic tissues are affected first

Wernicke’s syndrome

ataxia, confusion, nystagmus, ophthalmoplegia

Korsakoff’s syndrome

confabulation, psychosis, and mammillary body hemorrhage

beriberi

dry beriberi

peripheral neuropathy due to demyelination

symmetrical muscle wasting

no fluid retention

wet beriberi 

high-output cardiac failure (dilated cardiomyopathy)

edema

diagnosis

can be made by measuring increased transketolase activity after thiamine administration 

mechanism

thiamine is a cofactor necessary for the function of transketolase

diagnosis of thiamine deficiency is made by history

management

patients that present with thiamine deficienty should be treated with thiamine first

after thiamine has been administered, can then administer glucose in IV fluids

mechanism

thiamine is a cofactor for enzymatic steps in glycolysis

administering glucose before thiamine could further decrease thiamine levels for enzymes like transketolase which could exacerbate Wernicke-Korsakoff syndrome

Vitamin B₂ (Riboflavin)

•  Function
  • cofactor for
    • oxidation and reduction (e.g., FADH₂)
    • succinate dehydrogenase
  • precursor to FAD and FMN 
  • involved with many dehydrogenase enzymes
• Deficiency
  • causes
    • severe malnourishment
  • symptoms
    • cheilosis (inflammation of the lips and scaling and fissures at the corners of the mouth)
    • corneal vascularization
    • dry skin
• magenta-colored tongue

Vitamin B₃ (Niacin)

• Function 
  • constituent of NAD⁺and NADP⁺ (used in redox reactions)
  • derived from tryptophan
  • involved with many dehydrogenase enzymes 
  • synthesis requires vitamin B₂ and B₆
• Deficiency 
  • causes
    • diets low in tryptophan or niacin
      • corn staple diets
    • Hartnup disease
      • ↓ tryptophan absorption in kidneys and small intestine
    • malignant carcinoid syndrome
      • ↑ tryptophan metabolism in production of serotonin
    • INH therapy
      • ↓ vitamin B₆ leading to ↓ niacin synthesis
  • symptoms
    • glossitis
    • severe deficiency leads to pellagra (3 D’s) 
      • diarrhea, dermatitis, dementia
• Excess
  • causes
    • nicotinic acid given at high doses as hyperlipidemic treatment (raised HDL)
  • symptoms
    • facial flushing
      • mediated by prostaglandins, treated with aspirin
    • intrahepatic cholestasis
    • hyperglycemia
• hyperuricemia

Vitamin B₅ (Pantothenate)

• Function
  • component of coenzyme A required for many enzymatic processes
    • fatty acid synthase (fatty acid metabolism)
    • acyl transferases
    • pyruvate dehydrogenase (PDH)
    • α-ketoglutarate dehydrogenase (TCA cycle)
• Deficiency
  • rare
  • symptoms
• dermatitis, enteritis, alopecia, and adrenal insufficiency

Vitamin B₆ (Pyridoxine)

• Function 
  • converted to pyridoxal phosphate, a cofactor used in
    • transamination (e.g., ALT and AST in protein catabolism) 
    • decarboxylation reactions
    • glycogen phosphorylase
    • cystathionine synthesis
    • heme synthesis
  • required for the synthesis of niacin from tryptophan
• Deficiency
  • causes
    • INH (isoniazid) 
    • oral contraceptives
    • goat milk
    • chronic alcoholism
  • symptoms
• convulsions, hyperirritability, peripheral neuropathy, sideroblastic anemias, cheilosis or stomatitis

Vitamin B₁₂ (Cobalamin)

•  Function
  • cofactor for homocysteine methyltransferase 
    • transfers CH₃ groups as methylcobalamin
    • cofactor for homocysteine + N-methyl THF → methionine + THF
  • cofactor for methylmalonyl-CoA mutase
    • metabolism of propionate (odd-chain fatty acid degradation) at the conversion of methylmalonyl CoA → succinyl CoA
    • folate not directly involved in this pathway
    • megaloblastic anemia with an elevated methylmalonyl CoA indicates B₁₂ deficiency as opposed to folate  
  • metabolism of Val, Met, ILe, Thr
• Source
  • found only in animal products
  • several years of reserves stored primarily in the liver
• Deficiency 
  • causes
    • pernicious anemia
      • intrinsic factor required for absorption in the terminal ileum
      • B₁₂ not absorbed when intrinsic factor not produced from the parietal cells of the stomach
    • gastric bypass surgery
      • less intrinsic factor produced
    • resection of terminal ileum
      • e.g., Crohn’s disease
    • malabsorption
      • sprue, enteritis
    • bacterial overgrowth of terminal ileum
    • diphyllobothrium latum (parasite)
      • competes for B12 absoroption
    • vegan diets
    • use Schilling test to detect etiology of the deficiency 
      • differential process of radiolabeled B₁₂
        • oral B₁₂ + IM B₁₂
        • B₁₂ + intrinsic factor
        • B₁₂ + antibiotics
        • B₁₂ + pancreatic enzymes
  • symptoms
    • macrocytic, megaloblastic anemia
      • found also in folate deficiencies
    • hypersegmented PMNs
    • neurologic symptoms due to abnormal myelin
      • paresthesias and subacute combined degeneration 
        • dorsal columns of spinal cord degenerate causing loss of proprioception and vibration sensation
      • not found in folate deficiencies
      • could be reversible with administration of B₁₂
• severe symptoms and longer term B12 deficiency = more residual neurologic damage and less function regained

Folic Acid

• Function  
  • converted to tetrahydrofolate (THF), a coenzyme for 1-carbon transfer/methylation reactions
  • important for the synthesis of nitrogenous bases in DNA and RNA (thymidylate synthase)
    • recall: uridine + methyl group = thymidine
• Deficiency
  • most common vitamin deficiency in the United States
  • absorbed in the jejunum via the action of intestinal conjugase
  • causes
    • dietary deficiency
      • elderly
      • goat milk
    • seen in alcoholism and pregnancy
      • liver stores last three months
    • deficiency can be caused by several drugs
      • e.g. phenytoin, sulfonamides, methotrexate, EtOH
  • findings 
    • macrocytic, megaloblastic anemia
    • hypersegmented neutrophils
    • homocysteinemia
      • ↑ risk of DVT and atherosclerosis
    • no neurologic symptoms + normal methylmalonic acid level (as opposed to vitamin B₁₂ deficiency)
    • deficiency in pregnancy causes fetal neural tube defects
• supplemental folic acid in early pregnancy reduces risk

Biotin

• Function 
  • cofactor for carboxylation enzymes (adds a 1-carbon group) 
    • pyruvate carboxylase
      • pyruvate (3C) → oxaloacetate (4C)
      • gluconeogenesis
    • acetyl-CoA carboxylase
      • acetyl-CoA (2C) → malonyl-CoA (3C)
      • fatty acid synthesis
    • propionyl-CoA carboxylase
      • propionyl-CoA (3C) → methylmalonyl-CoA (4C)
      • odd-carbon fatty acids, Val, Met, Ile, Thr catabolism
• Deficiency
  • relatively rare
  • causes
    • antibiotic use
    • excessive ingestion of raw eggs
      • contains avidin which binds biotin
  • symptoms
• dermatitis, alopecia, enteritis, lactic acidosis

Vitamin C (Ascorbic Acid)

• Function  
  • antioxidant
    • regenerates vitamin E
    • ↓ oxidation of LDL
  • keeps iron in Fe²⁺ reduced state
    • ↑ intestinal absorption
  • collagen synthesis
    • essential for hydroxylation of proline and lysine
    • prolyl and lysyl hydroxylases
    • addition of hydroxyl group allows for hydrogen bonding between fibers
    • without cross-linking triple helix shape cannot form
  • synthesis of norepinephrine
    • necessary for dopamine β-hydroxylase
      • converts dopamine to NE
  • hepatic synthesis of bile acids
  • keeps THF in reduced form
  • protects against nitrosylation of amides
    • occurs in the stomach with presence of food preservatives
    • nitrosamines/amides are carcinogenic
• Source
  • found in fruits and vegetables
  • British sailors carried limes to prevent scurvy
• Deficiency
  • causes
    • diet lacking citrus fruits and green vegetables
    • infants on formula that is boiled too long
      • excessive heat destroys vitamin C
    • cigarette smoking
  • symptoms
    • scurvy   
      • swollen gums, bruising, perifollicular hemorrhage, poor wound healing, glossitis, ↑ bleeding time
      • anemia due to combined iron and folate deficiency
    • infantile scurvy
      • 2-10 months
      • excessively boiling formula
• Excess
  • symptoms
    • formation of renal calculi made from calcium oxalate (vitamin excreted as oxalate)
    • diarrhea, nausea, vomiting
• excess iron absorption in those predisposed (hemochromatosis, repeat blood transfusions)

S-Adenosylmethionine (SAM)

• Not a vitamin but an important cofactor
• Synthesis
  • ATP + methionine → SAM
  • regeneration of methionine (and thus SAM) is dependent on vitamin B₁₂ and folate
• Function
  • SAM transfers methyl units
    • similar to THF
• SAM is required for the conversion of NE to epinephrine