Water Soluble Vitamins Midterm #2 Flashcards
Generalities: Metabolism and Storage
only B12 and folate are stored in the body, in general water soluble vitamins are excreted rapidly and not stored. Depletion is more of a problem than toxicity.
Generalities: Toxicity
Only niacin and pyridoxine can become toxic at high concentrations. In general there are very few toxicities.
Generalities: Measuring body levels
water soluble vitamins are coenzymes for various common biochemical reactions and their status can be determined by measuring the appropriate enzyme activities. Typically enzyme activity is measured in the absence and the presence of exogenously added coenzyme and then determined if the patient needs more of the vitamin.
Vitamin B1
Thiamin
Vitamin B1 (thiamin): Structure
pyrimidine and thiamin ring. Thiazole is the “business end”. phosphorylation occurs at the alcohol group off the thiamin ring. Addition of one ATP forms TMP (thiamine monophosphoate) and addition of a second ATP forms TPP (Thiamine pyrophosphate).
Vitamin B1 (thiamine): Function
Metabolism of carbohydrates in glycolysis and TCA cycle. Cofactor for pyruvate dehydrogenase (glycolysis) and alpha-ketoglutarate dehydrogenase (TCA).
Vitamin B1 (Thiamine): Reactions
Oxidative carboxylation of alpha-keto acids
and transfer of alpha-ketols
Vitamin B1 (Thiamine): oxidative decarboxylation of alpha-keto acids enzymes
Pyruvate dehydrogenase complex
alpha-ketoglutarate dehydrogenase complex
Vitamin B1 (thiamine): pyruvate dehydrogenase reaction
Oxidative decarboxylation of alpha-keto reaction.
form acetyl-CoA intermediate for the TCA cycle and NADH
Vitamin B1 (Thiamine): alpha-ketoglutarate dehydrogenase reaction
Oxidative decarboxylation of alpha-keto acids
form succinyl CoA and NADH in TCA cycle.
Vitamin B1 (Thiamine): transfer of alpha-ketos reaction
used in the pentose phosphate pathway (pentose shunt in glycolysis).
Provides 5 carbon pentose sugars for DNA and RNA synthesis and also produces NADPH.
Runs both directions.
Vitamin B1 (Thiamine): Mechanism
All occurs on the thiamin ring. The 2-C loses a hydrogen atom to form a negative charge on the carbon and a positive charge on the nitrogen. The negative charged carbon can attack C=O to form a tetrahedral intermediate. Alpha-hydroxy-ethyl TPP is the intermediate with a two carbon structure attached and is used to move 2 carbon groups around.
Vitamin B1 (Thiamin): needs
Thiamin needs are proportional to caloric intake.
Vitamin B1 (Thiamin): measuring deficiency
Measure deficiency using erythrocyte transketolase assay
Vitamin B1 (thiamin): deficiency in alcoholics
About 40%-50% of chronic alcoholics are deficient. Low intake and alcohol affects the conversion of thiamin to TPP. Also, increased urine flow may cause thiamin washout. This includes fetal alcohol syndrome, which can be helped with supplementing the mother with thiamin.
Vitamin B1 (thiamin): Signs of deficiency
Early signs: anorexia, nausea, vomiting, fatigue, weight loss, nystagmus, tachycardia.
Late signs: beriberi (polyneuritis). Wet beriberi includes cardiac issues including cardiac edema, and enlargement of heart.
Wernicke-Korsakoff syndrome
Vitamin B1 (thiamin deficiency)
neurological disorder resulting in impaired mental functioning usually requiring institutionalization. Symptoms include confusion, memory loss, confabulation, psychotic behavior, and maybe irreversible in part. Seen in alcoholics.
Vitamin B1 (thiamin): factors causing deficiency
Increased carbohydrate intake, i.e. TPN and alcoholics
Decreased absorption, i.e. ulcerative colitis and alcoholics
Decreased intake, i.e. poor diet, geriatrics, breast fed infant from B1 deficient mother
alcoholism
Vitamin B1 (thiamin): cellular uptake
Thiamin specific receptor in intestinal cells (hTHTR) which only recognizes thiamin, not TPP. Common to ingest thiamin in plants and TPP in meats, this has to be broken down to thiamin for uptake. Have been polymorphisms in the gene encoding hTHTR which may cause thiamin-responsive megaloblastic anemia.
Vitamin B1 (Thiamin): Source
Present in most tissues as TPP and plants as thiamin.
Rich sources include lean meat, especially pork, cereal grains, eggs, yeast, nuts.
Thiaminase in some raw fish and raw shellfish have an enzyme that can hydrolyze thiamin
In the milling or processing of rice and flour, thiamin is lost. Whole wheat or rice contains 10X the amount of thiamin as white. In the US most white flour, rice, pastas are “enriched” to restore thiamin levels. “Enriched” products also have added riboflavin, niacin, iron and folic acid.
Vitamin B1 (thiamin): Stability
labile at pH > 4 and when heated.
Vitamin B1 (thiamin): diagnosis of deficiency
increased pyruvate and lactate in plasma (because can’t form pyruvate) or the transkelotase activity in RBC. You compare the activity of the enzyme in the presence and absence of thiamine. If addition of thiamine increases activity that person is said to be deficient.
Vitamin B1 (Thiamin): Uses
- deficiency states - alcoholics
- thiamin responsive inborn errors of metabolism
- mosquito repellant - questionable efficacy
- Acute alcoholism - have to give IV or IM because don’t absorb well orally
- Alzheimer’s disease - huge dose, questionable efficacy
Vitamin B1 (Thiamine): Responisve inborn errors of metabolism
- Wernicke-Korsakoff: transketolase defect
- Maple Syrup urine disease: failure to decarboxylate branched chain amino acids defect
- Thiamin responsive megaloblastic anemia
- Hyperalanemia: unknown defect
- Hyperpyruvate acidurea: pyruvate dehydrogenase defect
Vitamin B1 (Thiamin): Toxicity
nontoxic on oral administration. Anaphylaxis have been observed in patients receiving repetitive parenteral doses.
Vitamin B1 (Thiamine): Patient Counseling
- needed to drive carbohydrates to energy
- rarely used as a single supplement, use a multivitamin
- special benefit in alcoholics at higher doses, responsive population
Vitamin B2
Riboflavin
Vitamin B2 (Riboflavin): Structure
- Oxidized form appears bright-yellow or orange.
- Riboflavin monophosphate, FMN, is produced from riboflavin in the gut mucosa
- Flavin adenine dianucleotide, FAD, is produced from FMN in the liver
Vitamin B2 (riboflavin): function
- Redox, tissue respiration, H transfer as flavin containing enzyme
- Oxidized FMN or FAD accepts two hydrogen ions to form the reduced colorless form FMNH2 or FADH2.
- Reduced form is used to oxidize double bonded carbons into a single bond
Vitamin B2 (riboflavin): Some enzymes that use flavin groups
succinate dehydrogenase, fatty acid acyl CoA dehydrogenase, glutathione reductase
Vitamin B2 (riboflavin): Important flavoproteins containing FMN
cytochrome C reductase, NADP cytochrome C reductase, cytochrome P450 reductase, flavin monooxygenase
Vitamin B2 (riboflavin): deficiency state
- Not usually seen in isolation but occurs in combination with other B vitamin deficiencies.
- Fatigue, cheilosis, glossitis, vascularization of cornea, dermatitis
- Vegans and teenagers may be low in B2 if dairy intake is low
- Low B2 intake may be a risk factor for cataract development
- Alcoholics are at risk due to low intake and low absorption
Vitamin B2 (riboflavin): source
milk, meats, leafy vegetables, eggs, yeast, “enriched” products
Vitamin B2 (riboflavin): Stability
usually > 30% destroyed by cooking, labile to light, more stable in acid than alkali in absence of light
Vitamin B2 (riboflavin): Use
- deficiency states: component of most multivitamins
- May help in migraine headache prevention - new use
- High intake (3 mg) may be associated with lower risk for cataracts - new use
Vitamin B2 (riboflavin): Patient counseling
- Normal to turn urine bright yellow in higher dose
- routine single dose supplementation not needed, use a multivitamin to get needed riboflavin
- Nontoxic
Vitamin B6
pyridoxal
Vitamin B6 (pyridoxal): Structure
- 3 vitamers: pyridoxine (P) is inactive, pyridoxal (PL) is active and pyridoxamine (PN) is active.
- PP is transformed to PLP through FMN and PNP is transformed to PLP through FMN. These are the phosphorylated forms of the three vitamers.
- Coenzyme form is PLP, pyridoxal-5-phosphate
Vitamin B6 (PLP): functions
- transamination
- decarboxylation
- sulfur amino acid metabolism
- methionine formation
- tryptophan metabolism to serotonin and niacin
- glycogen phosphorylase
- heme biosynthesis
- nuceic acid biosynthesis through SAM
Vitamin B6 (PLP): transamination function
example is glutamate-aspartate transaminase. Formation of external amine.
Vitamin B6 (PLP): decarboxylation function
examples include glutamic acid to GABA, 5-hydroxytryptophan to serotonin, histidine to histamine, and DOPA to dopamine
Vitamin B6 (PLP): DOPA therapy
DOPA to dopamine: B6 is contraindicated in levo-DOPA therapy because B6 enhances peripheral decarboxylation of levo-DOPA to dopamine which will not cross the blood brain barrier. Larobec contains no pyridoxone and can be used if multivitamin supplementation is desired for patients on levo-DOPA. The anti-Parkinson’s drug Sinemet contains levo-DOPA and carbidopa, a DOPA decarboxylase inhibitor and there is no interaction with pyridoxine.
Vitamin B6 (PLP): sulfur amino acid metabolism
- elevated homocysteine is an independent risk factor for cardiovascular disease and birth defects.
- PLP catalyzes the conversion of homocysteine to cystathionine
- and the conversion of cystathionine to alpha-ketobutyrate and cysteine
Vitamin B6 (PLP): Tryptophan metabolism to serotonin and niacin.
Tryptophan can either be converted to serotonin, PLP mediated or niacin through many steps some of which involve PLP.
Vitamin B6 (PLP): internal vs external imine
external imine forms ketone and NH2 on the pyridine ring. The internal imine forms an aldehyde on the ring and a amine. The PLP enzymes control which carbon gets attacked by oxygen by switching between the internal and external imine.
Vitamin B6 (PLP): iatrogenic deficiencies
- isoniazid: antituberculosis drug that forms a Schiff base with B6. Results in neuritis, convulsions. Treat with high levels of B6.
- 4-Deoxypyridoxine (experimental only): competitive inhibitor, symptoms include skin lesions on face, glossitis, stomatitis, convulsive seizures (possibly due to decreased GABA), anemia (possibly due to decreased heme synthesis)
- Oral contraceptives: older higher doses of progesterone, but generally not a problem now.
Folic Acid: Function
The folate cycle and methylation
- Forms purines through N10 formyl THFA
- Forms folinic acid, N5 formyl THFA, “Leucovoran” (all different names for same thing)
- Forms pyrimidines. Enzyme is thymidylate synthesis results in pyrimidine and DHFA
- Regenerates THFA through combination of N10 methyl THFA + homocysteine to get THFA and methionine
Folic Acid: Chemistry
Active coenzyme is THFA which is formed from a pteridine ring with PABA by DHFA reductase and NADPH to form DHFA. DHFA reductase and NADPH then convert it to the reduced active form THFA
Folic acid is a pteroyl monoglutamic acid and is fully oxidized and found in supplements but not found naturally
Reduced polyglutamates are found in animal and plant foods.
Vitamin B12
- CN, cyano- storage form found in vitamins
- OH, hydroxy- storage form found in vitamins
- CH3, methyl- active form of coenzyme
- CH2-adenosine, deoxyadenosine- active form of coenzyme
Vitamin B12: methyl transfer reaction
necessary for recycling of THFA (folic acid). to reform active cobalamin form of Vitamin B12 need convert homocysteine to methionine.
Vitamin B12: metabolism of odd chain fatty acids (mutase reaction)
B12 is a cofactor for mutase which converts methyl malonyl CoA into succinyl CoA which can be used in the TCA cycle. You can diagnose B12 deficiency because methyl malonyl CoA is excreted in the urine as methyl malonic acid in deficiency.
5-deoxyadenosyl cobalamin is the coenzyme form of B12 used in this reaction
Vitamin B5: Chemistry
peptide in diet that gets converted to CoASH (coenzyme CoA). Only the D enantiomer of CoASH has biological activity
Vitamin B5 ( Pantothenic acid): function
thioester bond, which is a high energy bond used to transfer acyl groups
Biotin: Structure
Bound to enzymes so dietary proteins must be digested to lysine-biotin (biocytin) which is hydrolyzed by biotinase to release biotin. An inborn error with a defect in biotinase is known.
Niacin: Chemistry
two active forms, niacin (nicotinic acid) and niacinamide, both are found in the diet. Coenzyme form is NAD (ADP attached) or NADP (ATP form). When you reduce the quartenary Nitrogen you get the reduced forms NADH and NADPH.
Niacin: Function
- Redox and electron transport: know reaction for exam. Take a single C-C bond and form a double C=C bond.
- Ribosylation of proteins in cell signaling and DNA replication and repair. NAD + protein –> niacin + ADP-protein
Vitamin C (ascorbic acid): structure
Vitamin C in the reduced form is an active coenzyme only in the L configuration. Addition of 2 electrons forms dehydroascorbic acid which is inactive but acts as a free radical scavenger. Metabolism of dehydroascorbic acid forms oxalic acid which is excreted and may result in kidney stones.
Vitamin C (ascorbic acid): function
- Dopamine –> norepinephrine through DBH, dopamine beta-hydrolase. Ascorbic acid is the cofactor
- proline –> hydroxyproline which is a major mechanism of collagen synthesis and is the reason why signs of scurvy are generally associated with impaired collagen synthesis.
- lysine hydroxylase –> collagen
- Folic acid –> THFA. Explains the reason we see macrocytic anemia in scurvy.
5 .Involved in the absorption of iron in the gut. Fe has to be in the 2+ form which is catalyzed by ascorbic acid, for absorption. Vitamin C acts as a chemical reductant.
- General antioxidant/free radical scavenger. Involved in preventing oxidation of LDL, vitamin E regeneration, and prevention of mutagenic compounds in gastric juices.
