Biochemistry Vitamins 1. Water soluble vitamins 2. Fat soluble vitamins

Biochemistry

Vitamins   1. Water soluble vitamins 2. Fat soluble vitamins

Objectives: 

To recognize vitamins by nameTo understand their distribution in various food sourcesTo understand their role in metabolismTo understand the signs and symptoms of diseases resulting from deficiencies

Vitamins

A group of organic nutrients required in small

quantities for a variety of biochemical

functions and which , generally , cannot be

synthesized by body and must therefore be

supplied in the diet.

Water soluble vitamins 

1. B-complex vitamins 

a) B-vitamins in energy metabolism Thiamine (B1) Riboflavin (B2) Niacin (B3) Biotin Pantothenic acid

 b) B-vitamins in methyl group metabolism conversions Folic acid Cobalamin (B12)

 c) B-vitamins in metabolic conversions Pyridoxine (B6) Pyridoxal Pyridoxamine

  2. Vitamin C

O-

O

O

H3CS

O

H3CCoA CO2+

pyruvate acetyl CoA

pyruvate dehydrogenase complex

Champe and Harvey, p. 106

O

H3C

O

O-

N

N

N+ S

H3C

NH2 H

HO

N

N

N+ S

H3C

NH2 CH

O

P OP O-

O

-OO

-O

H3C OH

N

N

N+ S

H3C

NH2 H

O

P OP O-

O

-OO

-O

CO2

thiamine (B1)

thiamine pyrophosphate TPP

first step in pyruvate dehydrogenase complex

+

Thiamine Food sources and distribution:

Whole grain, meats, legumes (peas, beans and lentils)  Signs and symptoms of deficiency

Beri-beri: severe deficiencyPrimarily in areas where polished rice is primary food sourceSymptoms include dry skin, irritability, disorderly thinking and progressive paralysisWet beriberi-cardiovascular symptoms, cardiac failure Infants: onset can be rapid, resulting in tachycardia and death(look to nutritional status of mother)

Wernicke-Korsakoff syndrome: Primarily associated with severe alcoholism.Symptoms include apathy, loss of memoryWandering eye movement

  Toxicities, contraindications, and other notes

Only known use in treating deficiencyCommonly given to alcoholics in ER(emergency room)Excess of any one B-vitamin can cause deficiency of others.

Rubin and Farber, Pathology - 2nd edition, p. 329

N

N

N

NH3C

H3C

O

H

O

CH2

OH

OH

OH

OH

CH2

OH

OH

OH

O P

O P

OO

N

NN

N

NH2

OHHO

O

-O

-O

N

N

N

NH3C

H3C

O

H

O

O

N

N

N

NH3C

H3C

O

H

O

H

H

FADH2

riboflavin (B2)

Flavin adenine dinucleotide FAD

Riboflavin  

Food sources and distribution:Milk, cheese, meat, leafy vegetables, breads, cereals

 Signs and symptoms of deficiency

Sore throat, glossitis, cheilosis (red lips)Anemia, neuropathy

 Toxicities, contraindications and other notes

Only known use in treating deficiencyExcess intake can cause yellow urineExcess can interfere with B1 & B6

Rubin and Farber, Pathology - 2nd edition, p. 331

N+

O

NH2

H

N+

O

O-

H

N+

O

NH2

N

NN

N

O

O

NH2

OHHO

OH

OH

O

O

P

P

O

OO-

O

-O

H NADH

N

O

NH2

H H

niacin (B3)

nicotinamide

nicotinamide adenine dinucleotide NAD+

H- = H+ + 2e-

niacin  Food sources and distribution:

Fish, meat, poultry, cereal, nutsTryptophan in diet can serve as alternative source

Signs and symptoms of deficiencyPellagra (pella agra: rough skin)3D’s: dermatitis, diarrhea, dementiared, swollen tongueobserved in chronic alcoholics

symptoms reverse within 24H of administration Toxicities, contraindications and other notes

Harnup’s disease: defective renal and intestinal transport of tryptophanFast growing tumors can exhaust tryptophan supplyExcess can cause high BP and uric acid, cardiac arrhythmiasCan lower cholesterol

Rubin and Farber, Pathology - 2nd edition, p. 330

N N

S

O

Enzyme

HHCO2

N N

S

O

Enzyme

HCO

-O

biotin

biotin  Food sources and distribution:

Can be synthesized by intestinal bacteriaFound in most foods

 Signs and symptoms of deficiency

Very rare, include dermatitis, muscle pain

Toxicities, contraindications, and notesChronic consumption of raw eggs can induce deficiency.Chronic inflammatory bowel disease can cause deficiency.

N

NN

N

O

NH2

OH

OH

O

P

O

P

O

O-O

O O-

N CH3

CH3

OH

O

HO

N

SH

H

OHN CH3

CH3

OH

O

HO

O-

pantothenic acid

coenzyme A: CoA

acceptor site for acetyl group

pantothenic (B5) 

Food sources and distribution:UbiquitousEasily destroyed by heating

 Signs and symptoms of deficiency

Very rareNeuromuscular degeneration

 Toxicities, contraindications and other notes

Megadose can cause diarrhea and water retention

B-complex vitamins in energy metabolism and neuropathologies

Review B-complex vitamins and energy metabolism: Thiamine B1 TPP, pyruvate dehydrogenase Riboflavin B2 FAD, FADH2

Niacin B3 NAD+, NADH Pantothenic acid coenzyme A Biotin decarboxylation reactions (decarboxylase)

N

vitamin B6

OHNH2

OH

CH3

H

+

N

OHOH

OH

CH3

H

+

N

OHO

OH

CH3

H

+

N

OO

OH

CH3

H

+

O-O

-O

pyridoxine

pyridoxamine

pyridoxal

pyridoxal phosphate

vitamin B6 - catalyzed reactions

N

OO

OH

CH3

H

+

O-O

-O

pyridoxal phosphate

R

N

O

O-H

H

N

OO

CH3

H

+

O-O

-O

Schiff base

R

N

O

O-

H

Transamination:

Deamination:

Decarboxylation:

Condensation:

oxaloacetate + glutamate --> aspartate + alpha ketoglutarate

serine --> pyruvate

histidine --> histamine

glycine + succinyl CoA --> gamma-aminolevulinic acid

Pyridoxine (B6)  Food sources and distribution:

Meat, whole-grain breads and cereals, vegetables Signs and symptoms of deficiency

Skin lesionsConvulsive disorders resulting from low levels of GABANeeded for NAD+ synthesis

 Toxicities, contraindications and other notes

Excess can lead to sensory nerve destruction, loss of feeling in fingers, legsExtra pyridoxine needed when using ISONAZIDE for treatment of TBISONAZIDE binds covalently to pyridoxal phosphate

Champe and Harvey, p. 250

N

N N

N

O

H2N

H CH3

H2N

O

O-

O

O-

O

O-

NH2

6-methylpteridine

para-aminobenzoic acid, PABA

glutamate

N

N N

N

O

H2N

H CH2

HN

O

O

O-

O

O-

NH

+

+

folate, folic acid

5

10

S

H2N

O

ONH2

sulfanilamide

N

N N

N

O

H2N

H CH2

HN

O

O

O-

O

O-

NH

folate, folic acid

5

10

N

N N

N

O

H2N

H CH2

HN

O

O

O-

O

O-

NH

dihydrofolate, DHF

5

10

N

N N

N

O

H2N

H CH2

HN

O

O

O-

O

O-

NH

tetrahydrofolate, THF

5

10

H

H

HH

HH

N

N NH

HN

O

H2N

H CH2

HN

O

O

O-

O

O-

NH

tetrahydrofolate, THF

5

10

OH

NH2

O

O-

serine

N

N NH

HN

O

H2N

H CH2

N

O

O

O-

O

O-

NH

10-hydroxymethyl-THF

5

10

H

NH2

O

O-

glycineH2C

OH

H

H

N

N NH

N

O

H2N

H CH2

N

O

O

O-

O

O-

NH

5,10 methylene-THF

5

10H2C

- H2O

Stryer, Fig 29-16

Folic acid  

Food sources and distribution:Fresh green vegetablesCooking can destroy folic acid

 Signs and symptoms of deficiency

Hemolytic anemias

Toxicities, contraindications and other notes.Critical for pregnant womenMegadose can interfere with Zinc absorption.May interfere with antiepileptic meds (phenobarbitol)

Rubin E, Pathology, p1379

Goodman Gilman, A. The Pharmacological Basis of Therapeutics, p.1245

Champe and Harvey, p. 327

N

N NH

NO

H2N

H CH2

N

O

O

O-

O

O-

NH

5,10 methylene-THF

5

10H2C

N

N NH

NO

H2N

H CH2

HN

O

O

O-

O

O-

NH

5

10H3C

Methyl loading of methionine

5-methyl-THF

NH2

O

O-

SCH3

NH2

O

O-

SH

homocysteine methionine

methylcobalamin fromvitamin B12

Cobalamin (B12)  

Food sources and distribution:Synthesized only by microorganismsDeficiency usually results from absorption problem, not availability

 Signs and symptoms of deficiency:

Pernicious anemiaMegaloblastic anemiaNeurologic dysfunctionCan result in abnormal fatty acid accumulation in membranes

 Toxicities, contraindications and other notes

Substantial stores of B12 are found in the body.Could take years to develop deficiency.Caution with patients who have had GI(gastro-intestinal) surgery.

Rubin and Farber, p. 1020

Vitamin C Food sources and distribution:

Citrus fruits, potatoes Signs and symptoms of deficiency:

Scurvy results from deficiency in collagen hydroxylationResults in spongy gums, loose teeth and bleeding under the skin

 Toxicities and contraindications:

Can cause oxidation, particularly in presence of free metalsCan be toxic with hemodialysis patients, iron storage diseasesAscorbate is metabolized to oxalate which can form insoluble precipitates with Ca++Result in low Ca++, kidney stones, heart deposits.

OO

OH

OH

HO OH

vitamin C: ascorbic acid

O

NHN

O

HN

O

NHN

O

HN

OH

proline hydroxyproline

sugar attachment site

Vitamin C and collagen synthesis

Rubin and Farber, Pathology - 2nd edition, p. 333

2 H2O2

HO

Vitamin C and hydroxyl radical formation

H2O2 + Fe2+ Fe3+ + HO + HO-

2 O2- + 2 H+ H2O2 + O2

superoxide hydrogen peroxide

superoxide dismutase

2 H2O + O2

catalase

Fenton reaction

ascorbic acid

DNA damage

lipid peroxidation

Review: Diseases associated/resulting from deficiencies in water soluble vitamins: BeriBeri: Vit B1 Wernicke-Korsakoff syndrome: Vit B1 Pellagra: Vit B3 Pernicious anemia: B12 Megaloblastic anemia: B12  Scurvy: Vit C

Fat-soluble vitamins 

Vitamin A 

Vitamin D 

Vitamin E 

Vitamin K

Vitamin A 

Food sources and distribution:Low fat dairy products, deep yellow, orange vegetables

Function: Vitamin A(retinol) is the precursor of retinel, the light-sensitive group in rhodopsin and other visual pigments.

Signs and symptoms of deficiency:Night blindness, dry eyes and skinSlow growth in childrenLowered resistance to infection

 Toxicities and contraindications:

Overdose can result in dry skin, headacheCan result in birth defects in pregnant womenCan cause liver damage

 Vitamin A derivatives (isotretinoin, accutane) can cause

birth defects and has been associated with suicide.

CH3

CH3CH3

CH3 CH3

CH3 CH3 CH3

H3C

H3C

CH2OH

CH3

CH3CH3

CH3 CH3

-carotene

all-trans-retinol

Rubin and Farber, Pathology - 2nd edition, p. 328

http://www.cnn.com/2002/US/01/08/plane.suicide.mother/index.html

Goodman and Gilman, The Pharmacological Basis of Therapeutics, p. 1599

Vitamin D 

Food sources and distribution:Egg yolks, fortified milk, fish oil, sun exposure

Function: A metabolite of vitamin D is a hormone that regulates the metabolism of calcium

and phosphorus.

Signs and symptoms of deficiency:Rickets in childrenOsteomalacia (osteoporosis) in adults

 Toxicities and contraindications:

The most toxic of vitamins in excessCalcium deposits in heart, hypertension, high cholesterolFragile bones

HO

HO

UV light

7-dehydrocholesterol

cholecalciferol (vitamin D3)

OHHO

(acts as a hormone-transcription factor activating expression of Ca++-binding proteins in intestine and bone)

liver hydroxylation

kidney hydroxylationactivated by parathyroidhormone when Ca++ is low

Vitamin D

1,25 dihydroxy

1

25

Robbins, Pathologic Basis of Disease – 5th Edition, p. 1221

Vitamin E 

Food sources and distribution:Poultry, seafood, seeds, nuts, whole wheat

Function:  Reacts with and neutralizes reactive oxygen species such as hydroxyl , radicals before they can oxidize unsaturated membrane lipids, damaging cell structure(antioxidant)

Signs and symptoms of deficiency: very rare , Unknown in humans, in animal may cause infertility Toxicities and contraindications:

Excessive bleeding, reduced sexual function

vitamin E

O

CH3

CH3

HO

H3C CH3H3C

-tocopherol

Vitamin K Food sources and distribution:

Made by intestinal bacteriaSpinach, leafy vegetables, oats, bran, potatoes

 Function: required for normal blood clotting(blood coagulation)

Signs and symptoms of deficiency:Excess bleeding, bleeding gums

 Toxicities and contraindications:

Jaundice in infants

O

O

vitamin K

menaquinone (vitamin K2)

required for the carboxylation of glutamate to -carboxyglutamate

allows proteins to bind calcium

N

OH

O-

O-

O

O

Ca++

important in blood clottingnewborn infants usually get a vitamin K shot