Enzyme Cofactors v1

8/6/2019 Enzyme Cofactors v1

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Reading material

Principles of Biochemistry with a HumanFocus by Garrett and Grisham, First

Edition, 2002, pages 453-468

Handbook of NonPrescriptions Drugs,

11th edition, Chapter entitled Nutritional

Products by Loyd V. Allen, Jr.


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Vitamins

a group of organic compounds needed in smallquantities in the diet for normal activity oftissues

between 14 20 substances have been identifiedas vitamins

many vitamins act as cofactors, coenzymes or

prosthetic groups for enzymes most vitamins are derived from diet

no calories are derived from vitamins


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Vitamins

first vitamin discovered was thiamine orB1 the term vitamin is derived from the fact

that the substances are needed for life(vita) and because thiamine happened tobe an amine the term was coined as such

however, not all vitamins are amines ornitrogen containing compounds


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Vitamins

vitamin requirements are usuallyexpressed as RDAs (recommended

dietary allowances)

guidelines are provided by 2

organizations:

the Food and Nutrition Board of the NationalAcademy of Sciences- National Research Council

the Food and Drug Administration (FDA)


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RDAs

applications of RDAs include: evaluating the adequacy of the national foodsupply

establishing standards for menu planning

establishing nutritional policy for publicinstitutions/organizations and hospitals

evaluating diets in food consumption studies

establishing labeling regulations

setting guidelines for food product formulation

developing materials for nutritional education


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RDAs

RDAs have limitations: they are too complex for direct consumer use

they do not state ideal or optimal levels of intake

the allowances for some categories are based onlimited data

the data on some nutrients in foods is limited

they do not evaluate nutritional status

they do not apply to seriously ill or malnourished

patients


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Vitamin deficiencies

primary food deficiency crop failure food storage loss

food preparation loss diminished food intake

poverty

anorexia food fadism

chronic diseases


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Vitamin deficiencies diminished absorption

absorption defect

parasites

malignancies

increased requirements

rapid growth increased physical activity

pregnancy

hyperthyroidism

increased loss drug therapy

diuresis

lactation


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Vitamin lossLoss is seen mainly in storage or food preparation

Vitamin A: sensitive to oxygen and light

Vitamin D: usually little loss Vitamin E: sensitive to oxidation especially

when heated or with alkali

Vitamin K: sensitive to acids, alkali, light andoxidizing agents

Vitamin C: very sensitive to oxidation,

especially when heated in contact with metals Vitamin B complex: water solubility results in

loss in cooking water

Riboflavin is sensitive to light


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Vitamins

Vitamins are typically divided into 2groups:

The fat soluble vitamins

A, D, E, and K

The water soluble vitamins

The B vitamins (B1, B2, B3, B6, B7, B12 andpantothenic acid)

Ascorbic acid (vitamin C)


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Bogus vitamins

Vitamin B4 adenine Vitamin B10 identical with folic acid

Vitamin B11

Vitamin B15 pangamic acid

Vitamin B13 orotic acid

Vitamin B17 laetrile Vitamin B19 wormsers secret formula


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Cofactors

provide chemical teeth for enzymes sometimes referred to as coenzymes

enzymes: proteins with catalytic activity

simple enzymes: large protein (polypeptide) that

catalyzes a reaction. The enzyme gets all the tools

(chemical teeth) it needs from the amino acids.

However, there are only 20 different amino acids conjugated enzymes : apoenzyme + cofactor =

holoenzyme


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EXAMPLE:Proteases: enzymes that cleave

peptide bonds

N

N

N

H

R

O

H

R'

O

H

N

OH

H

R

O

+ H2N

N

R'

O

H

H2O

protease

Enzymes perform catalytic reactions such as hydrolysis; the

side chains of amino acids participate in the reactions


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CH2OH

CH2

N

HN

CH2-COOH

all these tools come from amino acidsin the protein active site

Usually electron-rich

side chains are involvedin the catalysis

Aliphatic chains are

normally involved in

hydrophobic interactions

example of a simple enzyme

A serine protease enzyme such as chymotrypsin


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COO- OHN

N

H

ASP HIS SER

COOH O-N

NH

ASP HIS SER

R NH

O

R'

COOH ON

NH

ASP HIS SER

HN O-

R

R'

COO- OHN

N

ASP HIS SER

R

O

R' NH2

H2O

HYDROLYTIC CATALYSIS


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Example of a conjugated enzyme

N

N

R

O

H

H

N

R'

O

Zn+2

OH

cofactor needed for reaction

PRODUCTS + ENZYME

Zinc protease suchas ACE


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Cofactors

all water-soluble vitamins with the exception ofvitamin C are converted/activated to cofactors

only vitamin K of the fat-soluble vitamins isconverted to a cofactor

not all vitamins are cofactors; i.e., lipoic acid isnot a vitamin

cofactors may also act as carriers of specificfunctional groups such as methyl groups andacyl groups


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The water soluble

vitamins


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Pantothenic acid (vitamin B5)

CH2HO C

CH3

CH3

CH

OH

C N

O

CH2

H

CH2 COOH

First recognized in 1933 as a growth factor for yeast (Roger

J. Williams)


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Pantothenic acid

a yellow viscous oil (free acid) stable to moist heat (not to dry heat) and

to oxidizing and reducing agents

hydrolyzed in acid or alkaline medium

sources (numerous): liver, kidney, eggs,

lean beef, milk, molasses, cabbage,cauliflower, broccoli, peanuts, sweetpotatoes, kale (derive its name from

everywhere)


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Pantothenic acid

serves in its activated form as the cofactor for

coenzyme A (CoA) and the acyl carrier protein (ACP)

first phosphorylated by ATP to 4-

phosphopantothenate

next is the formation of 4-phosphopantetheine by

addition of cysteine and decarboxylation

adenylation by ATP forms dephospho-CoA

phosphorylation to the 3-OH of the ribose generates

CoA (coenzyme A)


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HH

OPO3OH

H H

O

N

NN

N

H2C

O

PO

O

O-

PO O-

O

N

OH

N

O

H

N

O

H

SH

NH2

Coenzyme A

N

S CH3

O

O

H

Acetyl CoA


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Coenzyme A

performs a vital role by transporting acetyl

groups from one substrate to another

the key to this action is the reactive thioester

bond in the acetyl form of CoA the thioester bond is stable enough that it can

survive inside the cell, but unstable enough that

acetyl-CoA can readily transfer the acetyl

group to another molecule


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N

CH3

H3C

H3C

OH

N

CH3

H3C

H3C

O CH3

O

acetyl CoA CoA acetylcholinecholine

Example of an acetylation reaction

Acetylcholine is an important neurotransmitter in

the autonomic nervous system (cholinergic) and in the brain


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Pantothenic acid

Deficiency: rats

graying of hair/fur in black rats

dermatitis

inflammation of nasal mucosa hemorrhage of adrenal cortex

humans

has not been encountered or extremely rare difficult to induce with either synthetic diets

and/or with antagonists (omega-methylpantothenic acid


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Pantothenic acid vague symptoms in human deficiency:

numbness and tingling in feet burning foot fatigue

GIT disturbances

available pharmaceutically as calciumpantothenate (d-isomer) and as racemicmixture

5 - 7 mg/day appear to prevent signs of

deficiency appears to be non-toxic (up to 10-20 gm have

been tolerated)


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Thiamine

N

N

NH2

H3C

CH2 NS

H3C

CH2-CH2-OH

THIAMINE

Vitamin B1; antiberi-beri vitamin; antineuritic factorwas the first water soluble vitamin discovered (Eijkman)


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Thiamine has the odor and flavor of yeast

slowly destroyed by moist heat; more

rapidly destroyed in a basic medium than

in an acid one source: whole cereals and grains; yeast;

organ meat pharmaceutical products use the

hydrochloride or mononitrate salts


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Thiamine

active form is thiamine pyrophosphate (formed

by the action of thiaminediphosphotransferase)

involved in the oxidative decarboxylation ofpyruvic acid and -ketoglutaric acid

involved in the transketolase reactions of thetriose phosphate pathway

also required for nerve function (unrelated tocoenzyme activity)


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Conversion of thiamine to TPP


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Typical reactions catalyzed by

TPP


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Reactions in which thiamine

pyrophosphate is a cofactor

Pyruvate decarboxylase Alcohol fermentation pyruvate to acetaldehyde

Pyruvate dehydrogenase Synthesis of acetyl-CoA

Alpha-ketoglutarate dehydrogenase Citric acid cycle

Transketolase reaction Carbon-fixation reactions of photosynthesis

Acetolactase synthetase Valine, leucine biosynthesis


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Thiamine pyrophosphate

the key portion of this cofactor is the

thiazolium ring with its acidic hydrogen

the hydrogen is removed by the enzymeforming an ylid (anion next to cation)

the anion can then react with carbonyl groupsin such molecules as pyruvate

the pyrophosphate functionality acts as achemical handle which holds the cofactor inplace within the enzyme

thiazolium ring


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N

N

NH2

NS

C

H3C

H

H2CH2C O P

H3C

O

O

O-

P O-

O

O-

thiazolium ring

thiamine pyrophosphate

N

N

NH2

NS

C

H3C

C

H2CH2C O P

H3C

O

O

O-

P O-

O

O-

OH

H3C

H

Hydroxyethyl thiamine pyrophosphate

CH3

ClCH3

Cl

H

O

O-


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N

SH

N

S

acidic hydrogen

O

pyruvate

N

S

CH3

Cl

HO

O-O

N

S

CH3

Cl

OH

- CO2

N

S

CH3 N

S

CH3

Cl

OH

resonance

ylid

H

O

H

H3C H

O

+ ylid

H+

acetaldehyde

Chemical mechanism for

action of B1 in pyruvate

dehydrogenase


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C

CH2OH

C

O

HO H

CH OH

CH2-OPO3H2

C

CH OH

CH OH

CH2-OPO3H2

C

OH

OHH

D-xylulose-5-phosphate D-ribose-5-phosphate

C

C OH

CH OH

CH2-OPO3H2

H OH

C

H

HHO

C

CH2OH

O

C

C OHH

OH

CH2-OPO3H2

+

septulose-7-phosphate

3-phosphoglyceraldeh

transketolase

TPP

Transketolase reaction



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C

CH2OH

C

O

HO H

CH OH

CH2-OPO3H2

D-xylulose-5-phosphate D-erythrose-4-phosphate

C

C OHH

OH

CH2-OPO3H2

+

3-phosphoglyceraldehyd

transketolase

TPP

C

CH OH

C

OH

OHH

CH2-OPO3H2

CH OH

C HHO

C

CH2OH

O

CH OH

CH2-OPO3H2

D-fructose-6-phosphate

These reactions provide a link between the pentose phosphate pathway and

glycolysis

Activity of erythrocyte transketolase is commonly used as an index ofthiamine deficiency


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Thiamine deficiency

earliest symptoms of thiamine deficiencyinclude:

constipation

appetite suppression nausea

mental depression

peripheral neuropathy

fatigue


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Thiamine deficiency (severe)

beri-beri (once associated with whitepolished rice diets and with highly milledwheat diets)

2 clinical types dry beri beri or neuritic beriberi associated with polyneuropathy (depressed peripheral

nerve function, sensory disturbance, loss of reflexes

and motor control and muscle wasting wet beri beri or cardiovacular beriberi

edema, congestive heart failure


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N

N

NS

OH

H3C H3C

CH2-CH2-OH

OXYTHIAMINE

NH2

H3C

N

H3C

CH2-CH2-OH

NEOPYRITHIAMINE

These 2 compounds are potent antithiamine agents which maybe used to induce symptoms of vitamin B1 deficiency in selected

animals. Oxythiamine competitively inhibits thiamine pyrophosphate

and becomes active after phosphorylation; neopyrithiamine

prevents the conversion of thiamine to thiamine pyrophosphate


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Other clinical applications Alcohol neuritis (peripheral neuropathy)

Sharp burning pain in the feet

Deep muscle tenderness with numbness

Coarse tremors, foot drop

Wernickes encephalopathy Results from degeneration of basal ganglia due to

chronic/heavy use of alcohol

Rigidity of extremities

Complete or partial ophthalmoplegia

Sleep disturbances

Nausea and vomiting


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Other clinical applications Korsakoffs syndrome or psychosis

Also a complication of chronic/heavy use of alcohol

Usually follows DTs (delirium tremens)

Memory loss

Delusions Disorientation

Ocular palsies

Combined Wenicke-Korsakoff syndrome

Pregnancy neuritis

Certain gastrointestinal disorders


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Requirement for thiamine

Based on energy needs

0.3 0.6 mg/1000 calories

Increased requirements:

Pregnancy and lactation Eating large amounts of raw sea food (clams)

contain thiaminase

Stress situations (high level of exercise, fever,hyperthyroidism)

Drinking large quantities of tea (containsantagonist)

i i


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Thiamine assay

biologic assay in animals time consuming

and costly (curative or protective)

microbiologic using bacteria which require

thiamine for growth

chemical/fluorescent assay conversion ofthiamine to thiochrome by alkaline ferricyanide

N

N

N

N SH3C

CH 2-CH 2-OH

CH 3THIOCHROME


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Lipoic acid lipoic acid is a co-factor found in pyruvate

dehydrogenase and -ketoglutaratedehydrogenase, two multienzymes involved in-keto acid oxidation

lipoic acid functions to couple acyl grouptransfer and electron transfer during oxidationand decarboxylation of-ketoacids

no evidence exists of a dietary lipoic acidrequirement in humans; therefore it is notconsidered a vitamin

S S SH HS


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S S

H2C

CH2

CH

COOH

SH HS

H2C

CH2

CH

COOH

S S

H2C

CH2

CH

C

N

O

H

CH

NH

C O

lipoic acid, oxidized form lipoic acid, reduced form

lipoamide complex (lipoyl-lysine conjugate)

Lipoic acid exists in 2 forms: a closed-ring disulfide form and

an open-chain reduced form; oxidation-reduction cycles interconvert

these 2 species; lipoic acid exists covalently attached in an amidelinkage with lysine residues on enzymes


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Riboflavin vitamin B2, lactoflavin (ovo, hepato, verdo),

vitamin G a heterocyclic flavin linked to ribose analogous

to the nucleosides in RNA

orange-yellow fluorescent compound found in significant quantities in green leafy

vegetables, milk and meats

heat stable, but easily destroyed by light

recommended intake is related to energy intake(kcal) RDA 1 2 mg/day

dimethylisoalloxazine


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N

N

N

NH 3C

H 3C

O

C

O

H

C

HH

C

H OH

C

H 2C

H OH

H OH

OH

RIBOFLAVIN

y

ring system confers some

degree of planarity to themolecule and also color

(yellow)

Decomposition of riboflavin


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N

N

N

NH3C

H3C

CH3

O

H

O

LUMIFLAVIN

(produced by photochemical cleavage

of riboflavin under alkaline conditions)

N

NH3C

H3C

CH3

O

COOH

+ UREA

NHCH3

NH2H3C

H3C

OH-

OH-

NH

N OO

O

O

H

alloxan

4-amino-1,2-dimethyl

5-methylaminobenzene


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Riboflavin 2 cofactors are involved:

riboflavin phosphate (flavin mononucleotide,FMN)

flavin adenine dinucleotide (FAD)

involved in the metabolism ofcarbohydrates, fats and proteins (flavin

dehydrogenases/flavoproteins) hydrogen carriers in the respiratory

chain


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N

N

N

N O

O

H

H3C

H3C

H2C C C C C O

H

OH

H

OH

H

OH H

H

P O

OH

O

P O

O

OH

CH2

O

N

N

N

N

NH2

OH OH

H H

HH

FLAVINE ADENINE DINUCLEOTIDE


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reduced substance

oxidized substance

FAD

FADH2

cytochrome electron

system (electron transport chain)

dehydrogenases

Riboflavin


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Riboflavin

N

N

N

N O

H

O

H3C

H3C

N

N

N

N O

H

O

H3C

H3C

H

H

FAD (oxidized form) FADH2 (reduced form

hydrogen additionoccurs in 2 steps


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Riboflavin Enzymes utilizing riboflavin cofactors:

NADH dehydrogenase

succinate dehydrogenase

d and l-amino acid oxidases

pyridoxine-5-phosphate oxidase

glutathione reductase

xanthine oxidase In some enzymes, the cofactor is covalently

bonded to an amino acid (dehydrogenases)


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Dehydrogenase reaction

CH2

CO2-

CH2

CO2- FAD FADH2

succinate

dehydrogenase C

CO2-

C

CO2-

H

H

succinate fumarate


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Amino acid oxidases

C

R

NH3+H

CO2-

H2O NH3

FMN FMNH2

R

C O

CO2-

most amino acids (except serine, threonine, basic, and dicarboxylic acids)can be deaminated by L-amino acid oxidases

Xanthine oxidase


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Xanthine oxidase

N

N N

N

OH

H

N

N N

N

OH

H

HO

N

N

N

N

OH

HHO

OH

hypoxanthine xanthine uric acid

xanthine oxidase

Xanthine oxidase is a flavoprotein which also contains Fe and Mo


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Fatty acyl-CoA desaturase

H H

R

H

SCoA

O

R

H

SCoA

OH

FADFADH2

fatty acyl-CoA desaturase

Important step in the biosynthesis of unsaturated fats; thisreaction is actually more complex than shown here and

involves other cofactors, but FAD is a key cofactor for the

enzyme


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Riboflavin deficiency seldom seen in industrialized societies

deficiency when seen: cheilosis (vertical fissure in the lips)

angular stomatitis (craks in the corner of the mouth)

glossitis photophobia

seborrheic dermatitis

normochromic normocytic anemia

usually encountered along with pellagra (niacin deficiency)

newborns treated for hyperbilirubinemia by phototherapy(riboflavin is unstable to light)


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Biotin

NN

S

O

H H

HH

(CH2)4-COOH

BIOTIN


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Biotin an imidazole sulfur containing compound

sometimes referred to as vitamin B7 or vitamin H

widely distributed in foods (liver, kidney, milk,

molasses) a large portion of the daily need of biotin is met by

synthesis by intestinal bacteria

deficiency is usually the result of a defect inutilization rather than simple dietary deficiency


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Biotin

like lipoic acid, biotin is converted to its

coenzyme form (called biotinyllysine or

biocytin) by formation of a covalent

amide bond to the nitrogen of a lysineresidue

like lipoic acid it performs a highlyspecialized function : adds a carboxyl

group to substrates


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Biotin biochemical role: carbon dioxide

fixation

two step process:

1. Binding of CO2 to biotin N-carboxybiotin

2. Transfer of CO2 to a substrate

Activation of biotin requires enzyme,CO2, ATP and Mg

++


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BiotinBiotin-dependent enzymes:

Pyruvate carboxylase (synthesis of oxaloacetate

for gluconeogenesis and replenishment of the

citric acid cycle)

Acetyl CoA carboxylase (fatty acid biosynthesis)

Propionyl-CoA carboxylase

-methylcrotonyl-CoA carboxylase holocarboxylase synthase (multiple carboxylase)

Reactions involving biotin enzymes


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CH3C

O

CO2- CCH2

O

CO2--O2C

pyruvate oxaloacetate

CH3C

O

SCoA CCH2

O

SCoA-O2C

acetyl CoA malonyl CoA

CCH2

O

SCoAH3C

propionyl CoA

CCH

O

CO2--O2C

CH3

methylmalonyl CoA

HCO3- + NH4

+ + ATP CH2N

O

O P OH

OH

O

carbamyl phosphate


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Biotin deficiency:

quite uncommon

can be induced by feeding raw egg white (avidin)

avidin is a protein which binds tighly with biotin (MW

70,000) symptoms are: anorexia, nausea, muscle pain, fine scaly

desquamation of the skin

requirements: 150 200 mcg/day therapeutic use: in babies with infantile

seborrhea (cradle cap) and Leiners disease


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Pyridoxine (vitamin B6)

N

CH2OH

CH2OHHO

H3C

PYRIDOXINE

A pyridine derivative


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N

CHO

CH2OHHO

H3CN

CH2NH2

CH2OHHO

H3C

PYRIDOXAMINEPYRIXOXAL

Other forms of B-6

Collectively, pyridoxine, pyridoxal and pyridoxamine areknown as vitamin B6


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Pyridoxine vitamin B6, rat acrodynia factor,

antidermatitis factor widespread occurrence

pyridoxine: mostly in vegetable products pyridoxal and pyridoxamine: mostly in animal

products

pyridoxine is stable in acid solution, butunstable in neutral or alkaline solutions(destroyed by light)

N

HO

H3C

CH2OH

CH2OH


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pyridoxine

N

HO

H3C

CH2OH

CHO

N

HO

H3C

CH2OH

CH2-NH2

pyridoxal pyridoxamine

N

HO

H3C

CHO

CH2 O P

O

OH

OH

N

HO

H3C

CH2-NH2

CH2 O P

O

OH

OH

pyridoxal phosphate pyridoxamine phosphate

N

HO

H3C

CH2OH

COOH

pyridoxic acid


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Pyridoxal phosphate pyridoxine is converted to pyridoxal phophate

by phosphorylation and oxidation to thealdehyde

pyridoxal phosphate is then attached to the

holoenzyme via a covalent bond to a lysineresidue (a Schiffs base)

the Schiffs base bond is readily broken and

reformed this reversibility is very important in the

biochemical action of this cofactor


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NH

CH2OH

CH2OH

H3C

HO

NH

CH2OPO3

H3C

HO

NH

CH2OPO3

H3C

HO

HO

HN

OH

H

N

Biochemical functions

Able to catalyze the breakdown of amino acids


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Pyridoxal phosphateBiochemical functions:

1. Decarboxylation of amino acids

2. Transaminase reactions

3. Racemization reactions

4. Aldol cleavage reactions

5. Transulfuration reactions

6. Conversion of tryptophan to niacin

7. Conversion of linoleic acid into arachidonicacid (prostaglandin precursor)

8. Formation of sphingolipids

HO

HN H

Lys

HN H

R

O-

O

R

CO2H

NH2

Lys

NH2

ecarboxylation of


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NH

H3C

NH

H3C

HO

N

H

H3C

HO

N

R

H

N

H

H3C

HO

N

R

H

H

N

H

H3C

HO

N

R

H

H

H

H+

N

H

H3C

HO

N

Lys

H

H

R Lys

NH2

H

NH2

resonancestabilization

- CO2

mino acids


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Important transaminases ALT ( alanine aminotransferase)

formerly known as SGPT (serum glutamate

pyruvate transaminase)

alanine + alpha-ketoglutarate = pyruvate +

glutamate

increased serum level in liver injury


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Important transaminases AST (aspartate aminotransferase)

formerly known as SGOT (serum glutamate

oxaloacetate transaminase)

aspartate + alpha-ketoglutarate = oxaloacetate +

glutamate

elevated when heart and/or liver are damaged


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Important decarboxylases

SERINE ETHANOLAMINE ACETYLCHOLINE

TYROSINE DOPA DOPAMINE EPINEPHRINE

TRYPTOPHAN 5-HT SEROTONIN

HISTIDINE HISTAMINE

GLUTAMIC ACID GAMMA AMINOBUTYRIC ACID (GABA)

CYSTEINE CYSTEINE SULFINIC ACID TAURINE

- CO 2

- CO 2

- CO2

- CO 2

- CO 2

- CO 2

Mechanism for transamination

reaction


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N

C

N

C COO-H

R

H

H

N

C

H

N

C

R

COO-

aldimine ketimine

N

H

CH2

NH2

COO-C

O

R

alpha-keto acid

pyridoxamine phosph


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Pyridoxine deficiency:

difficult to produce in humans

may be accomplished artificially with a

pyridoxine antagonist (deoxypyridoxine) symptoms include: nausea and vomiting,

seborrheic dermatitis, depression and

confusion, mucous membrane lesions,peripheral neuritis, anemia


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Pyridoxine antagonists

N

N

NH-NH 2

Hydralazine (antihypertensive)

N

C

O NH

NH2

isoniazid (antitubercular)

O

N

OH2N

H

cycloserine (antitubercular)

CC

CH3 H

COOHHS

CH3 NH2

penicillamine (antirheumatic; Wilson's disease)

Pyridoxine can antagonize the antiparkinsonian use of

L-DOPA


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L-DOPA L-DOPA L-dopamine

L-dopamine

CO 2

Brain

B 6 stimulates

this reaction outsideof the brain

use carbidopa: an inhibitor of DOPA decarboxylase

in combination with DOPA: Sinemet 10/100 or Sinemet 25/250


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Pyridoxine deficiency can be monitored by measuring the level of

xanthurenic acid in the urine

this is related to a decrease in kynureninase

activity (pyridoxal phosphate is the coenzyme)

kynurenine, a breakdown product of

tryptophan is normally converted to kynurenic

acid but in B6 deficiency it is shunted to formxanthurenic acid


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XANTHURENIC ACID

N COOH

OH

OH


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Pyridoxine requirements:

children: 0.5 1.2 mg adults: 2.0 mg

pregnancy: 2.5 mg

Requirement for B6

is proportional to the level ofprotein consumption

therapeutic uses: deficiency

to counterract the effects of antagonists

certain rare forms of anemia

in women taking oral contraceptives (estrogen shiftstryptophan metabolism

COOHDiscovered in 1913 fromyeast; also known as

vitamin B3


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N

NICOTINIC ACID

N

CONH 2

NICOTINAMIDE

1915 1920: Irving Golberg

demonstrated that lack of niacin

causes pellagra

one of the simplest

vitamin; like B6 also

a pyridine derivative


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Oxidation of nicotine yields

i ti i id


89/186

nicotinic acid

N

N

H

N

COOH[OXIDATION]

HNO3

nicotine nicotinic acid

This reaction does not occur in vivo strictly a laboratory

reaction

Ni ti i id


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Nicotinic acid niacin, vitamin B3, niacinamide, antipellagra

vitamin both form are active: the free acid and the

amide sources: organ meat (largest source), fish,

yeast, dried fruit, nuts, cereal grains, somevegetables pellagra-inducing diets: corn meal, corn starch,

sweet potatoes, rice, syrup, pork fat (once a

common diet in southern states amongsharecroppers)

O

NH2

Coenzyme forms


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H

H2C

H

OHOH

H H

ON

NH2

O

H

O P O

O

O-

P

O

O-

O CH2

HH

OHOR

H H

O

N

NN

N

NAD - OXIDATION REACTIONS R = H

NADPH - REDUCTION REACTIONS R = PO3

Two cofactor forms of niacin: NAD and NADP; these cofactors

are not tightly held by the enzyme and may be reused for reactionafter reaction

Bi h i l f ti


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Biochemical function

N

C

NH 2

O

N

C

NH 2

O

HH

NAD +

or NADP +

+ H +

NADH + H +

or NADPH + H +

In the older literature NAD+ is referred to as DPN or coenzyme I

NADP+ is referred to as TPN or coenzyme II

O idi d d d d f


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Oxidized and reduced forms

Sparing action of tryptophan

Tryptophan can substitute for niacin: 60 mg of tryptophan


94/186

TRYPTOPHAN FORMYLKYNURENINE KYNURENINE

3-HYDROXYKYNURENINE3-HYDROXYANTHRANILIC ACID

NICOTINIC ACID

B6-dependent reaction

Tryptophan can substitute for niacin: 60 mg of tryptophanis equivalent to 1 mg of niacin; 60 gm of protein contains 600

mg of tryptophan which then represent 10 mg of niacin

CH

COOH

NH 2

N

CH 2

CH 2

O

CH

COOH

NH 2

N

H


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HC O

Htryptophan

N-formylkynurenine

CH 2

O

CH

COOH

NH 2

NH 2

CH 2

O

CH

COOH

NH 2

NH 2

OH3-hydroxykynurenine kynurenine

alanine

COOH

NH 2

OH

CO 2N

COOH

3-hydroxyanthranilic acid

blocked by deficiency of thiamine

blocked by deficiencyof riboflavin

blocked by deficiency

of pyridoxine

Pellagra


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Pellagra Early stages:

Anorexia

Indigestion

Muscle weakness

Reddened skin

Rough skin

Advanced stages 3 Ds of pellagra: dermatitis, diarrhea, dementia

Clinical uses of nicotinic acid


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Clinical uses of nicotinic acid pellagra symptoms from:

gastric ulcer or carcinoma diarrhea

isoniazid therapy

carcinoid syndrome

Hartnup disease (impairment of tryptophan absorption)

peripheral vasodilator (nicotinic acid ornicotinyl alcohol)

hypolipidemic agent (only nicotinic acid inlarge doses lowers both triglycerides andcholesterol (Niaspan, Nicobid)

Carcinoid syndrome


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a slow growing neoplasm of enterochromaffin cells(ileum, stomach, bronchus)

tryptophan metabolism is altered resulting in excessserotonin synthesis

symptoms include:

facial flushing edema of head and neck

abdomina cramps and diarrhea

asthmatic symptoms

cardiac insufficiency

urinary 5-HIAA (5-hydroxyindole acetic acid) is high (5-HIAA is a metabolite of serotonin; serotonin is derivedfrom tryptophan)

Cautions concerning the use of

nicotinic acid in large doses


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nicotinic acid in large doses as an acid, it can erode gastrointestinal mucosa

leading to ulceration it also causes a depletion of glycogen stores and

fat reserves in skeletal and cardiac muscle

additionally, there is an elevation in bloodglucose and uric acid production

for these reasons, nicotinic therapy is not

recommended for diabetics or persons whosuffer from gout

Ascorbic acid


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vitamin C; anti-scorbutic vitamin (scurvy)

structure is reminiscent of glucose produced in plants from glucose via the uronic

pathway

the enzyme gulonolactone oxidase convertsgulonolactone to ascorbic acid

exists in the enolic and ketonic forms

sources: citrus fruits, tomatoes, green peppers,strawberries, cantaloupe, cabbage, turnips,peas, lettuce and aspargus

ASCORBIC ACID AND

DEHYDROASCOBIC ACID


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DEHYDROASCOBIC ACID

HO

HO

O

O

CH

OH

CH2OH

O

O

O

O

CH

OH

CH2OH

Ascorbic acid


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Biochemical functions:

Production and maintenance of collagen Proline --------hydroxyproline

Lysine -------- hydroxylysine

Mitochondrial electron-transport chain (cytochromeC)

Metabolism of tyrosine

Tyrosine ----- p-hydroxyphenylpyruvic acid---- 2,5-dihydroxyphenylacetic acid (homogentisic acid)

Proline hydoxylase: (collagen formation)

O

O


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Dopamine-beta hydroxylase ( neurotransmitter formation)

N

N

HO

vitamin C; O2

proline hydroxylase

NH2HO

HO

NH2HO

HO

OH

dopamine norepinephrine

dopamine betahydroxylase

O2; Vitamin C

Anti-oxidant properties of vitamin C:

helps prevent damage to cellular proteins and DNA


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OOHO

OH

OHHO

OO

HO

OH

OO

O

Normal metabolic processes in the cell lead to the generation

of reactive oxidizing agents such as superoxide

Superoxide can react with and damage protein and DNA, leadingto cellular changes that can lead to premature aging and cancer

Vitamin C reacts with superoxide, thus preventing this damage

Ascorbic acid


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conversion of folic acid to THFA

hydroxylation reactions of cholesterol to cholic acid hydroxylation of tryptophan to 5-

hydroxytryptophan

regulation of cholesterol biosynthesis in the adrenalgland

aids in the absorption and utilization of iron

antioxidant properties may inhibit formation ofnitrosamines during digestion of protein

Ascorbic acid


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defiency: scurvy

hemorrhage from mucous membranes,mouth and GIT, skin and muscles

gingivitis: swelling, tenderness, redness andulceration of gums

loosening or loss of teeth

swelling of joints

rarefaction of bones and dentine

Ascorbic acid


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requirements:

children: 30 mg

adults: 40 80 mg

pregnancy: 100 mg

therapeutic uses

scurvy

idiopathic methemoglobinemia

questionable use: common cold


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Vitamin B12


109/186

Vitamin B12


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cyanocobalamin (Redisol)

hydroxocobalamin (Alpha redisol)

function

deficiency hematological sequelae

neurological sequelae

Vitamin B12


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synthesized by bacteria only

red in color, levorotatory and stable to heat commercially available either as cyano or

hydroxocobalamin

stored in the liver as the coenzyme absorbed only in the presence of the intrinsic

factor (a glycoprotein released by parietal cells)

transported to tissues via transcobalamin II present in foods such as liver, fish, eggs, milk

absent in vegetables and fruits

Vitamin B12


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by far the most complex vitamin in structure

made up of a planar corrin ring (4 pyrroles) the only vitamin that possesses a metal ion

(cobalt) as part of its structure

the major cofactor form of B12 isadenosylcobalamin or 5-deoxyadenosylcobalamin

small amounts of methylcobalamin also occur(intermediate in methyl transfer reactions)

Vitamin B12


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the corrin ring is similar to the porphyrin ring

system found in hemoglobin except that incorrin 2 of the pyrroles are linked directly(without methylene bridges)

the cobalt is coordinated to the 4 pyrrolenitrogens

one of the axial cobalt ligands is a nitrogen of

the dimethylbenzimidazole group the other axial ligand may be CN, OH, CH3 or

the 5-carbon of a 5-deoxyadenosyl group

N N

CH 3CH 3H2NCOCH 2CH 2

H3C

H2NCOCH 2

CH 2CONH 2

CH 2CH 2CONH 2

Co

CN

H3C

Hcorin nucleus cobalt coordinated


114/186

NNH2NCOCH 2

CH 3

H2C

CH 3

CH 3

CH 2

NH

O

CH 2CONH 2

O

H3C

P

O

O

O

OH

HO

N

N

CH 3

CH 3

CH 3

H

VITAMIN B 12

benzylimidazole


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Vitamin B12

biochemical functions (mediated by


116/186

( ycoenzymes)

mutase reaction (rearrangement reaction methylmalonyl CoA to succinyl CoA (lipid metabolism)

methylation reactions

uracil to thymine homocysteine to methionine

aminoethanol to choline

activation of amino acids for protein synthesis ribonucleotides to deoxyribonucleotides for DNA

synthesis in certain bacteria

Causes of B12

deficiency


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Pernicious anemia (autoimmune gastritis

against parietal cells - loss of intrinsic factor) rarely due dietary deficiency

N2

O/oral contaceptive drugs

intestinal parasite

gastrectomy

chronic gastritis

Schilling test

Diagnosis of B12

deficiency


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Schilling test

distinguishes deficiency caused by perniciousanemia with that caused by malabsorption

compares absorption in radiolabeled B12 with

intrinsic factor and radiolabeled B12 withoutintrinsic factor

in pernicious anemia the B12 with intrinsic factor

will be absorbed while the B12 by itself will not in malabsorption neither will be absorbed

Manifestation of B12 deficiency

macrocytic megaloblastic anemia megaloblasts are abnormal erythroid precursors in


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megaloblasts are abnormal erythroid precursors inbone marrow (most cells die in the bone marrow)

reticulocyte index is low hyperchromic macrocytes appear in blood

anemia reflects impaired DNA synthesis

other cells may be involved (leukopenia,thrombocytopenia

spinal cord degeneration (irreversible)

swelling, demyelination, cell death neurological disease

results from deficient methylmalonyl-CoA mutase

this cannot be treated with folic acid!!

Treatment of B12

deficiency


120/186

use IM cyanocobalamin or hydroxocobalamin

administer daily for 2 - 3 weeks, then every 2 -4 weeks for life

monitor reticulocytosis early to assure

treatment is working (reticulocyte count shouldgo up)

monitor potassium levels to ensure

hypokalemia does not occur due to excessiveRBC synthesis


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Folic acid


122/186

MOA

deficiency

use

drug interactions with folic acid

O COOH

Also known as folacin, vitamin M and pteroylglutamic acid

Widely distributed in leaves (foliage) of plants


123/186

N

N N

N

N

H

C N CH

H

OH

H2N

O COOH

COOH

FOLIC ACID

Chemically composed of pteroic acid (pteridine and PABA)

and glutamic acid

FOLIC ACID

b b d b b th ti d i t t


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absorbed by both active and passive transport

on the average we absorb 50 -200ug per day(about 10 -25% of dietary intake)

storage is in the form of 5-methyl THF (5 -20

mg) found in green vegetable, dietary yeasts, liver,

kidney

bacteria synthesize their own folic acid(dihydropteroate synthetase)

Folic acid

Bi h i l f ti


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Biochemical functions

one carbon fragment transfer (formyl,methyl, hydroxymethyl)

conversion of homocysteine to methionine

conversion of serine to glycine synthesis of thymidylic acid

synthesis of purines (de novo)

histdine metabolism synthesis of glycine

PURINE CARBONS

DERIVED via FOLATE


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N

N N

N

NH2

DNA

N

N N

N

O

DNA

H2N

H

ADENINE (A) GUANINE (G)

BIOCHEMICAL ACTIVATION OF FOLIC ACID

FOLIC ACID 7,8-DIHYDROFOLIC ACID (DHFA)


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TETRAHYDROFOLIC ACID (THFA)N5, N10-METHYLENE

TETRAHYDROFOLIC ACID

N5-FORMYL TETRAHYDROFOLIC ACID (LEUCOVORIN, FOLINIC

ACID, CITROVORUM FACTOR)

OTHER FORMS OF THFA: N 5-METHYL THFA

N 5-FORMIMIDO THFA

N10-FORMYL THFA

N5, N10-METHENYL THFA


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Deficiency of folic acid

I d t i t k


129/186

Inadequate intake

defective absorption (most common) sprue

gastric resection and intestinal disorders

acute and chronic alcoholism

drugs (anticonvulsants and oral contraceptives)

pregnancy pellagra

Deficiency of folic acid

abnormal metabolism of folates


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abnormal metabolism of folates

folic acid antagonists (dihydrofolate reductaseinhibibitors - methotrexate, pyrimethamine,

trimethoprim)

enzyme deficiency vitamin B12 deficiency

oral contraceptives

increased requirement

pregnancy, infancy

METHOTREXATE

H


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N

N N

N

NH2

H2

N

CH2N

CH3

N CH

H

O

(CH2)2-COOH

COOH

METHOTREXATE

Inhibits enzyme dihydrofolate reductase (DHFR) which is

necessary for maintaining pool of reduced folates requiredfor DNA synthesis

METHOTREXATE

also known as amethopterin or MTX

a potent inhibitor of dihydrofolate reductase whicht l th i f f li id t t t h d f li


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catalyzes the conversion of folic acid to tetrahydrofolicacid (THFA)

THFA acts as an acceptor of a one-carbon unit fromeither formate or formaldehyde

5-formyl THFA is also known as folinic acid or thecitrovorum factor (leucovorin)

THFA one-carbon carriers are important in the synthesisof purines, thymine, choline, and other important cellularconstituents

MTX is used in treating acute lymphocytic leukemia inchildren, choriocarcinoma, osteogenic sarcoma,

carcinomas of the head, neck, bladder and testis in lower doses: treatment of psoriasis and rheumatoid

arthritis

N

N

NH 2

CH 2CH 3

H2N Cl

PYRIMETHAMINE

N

N

CH 2

OCH 3

OCH 3

OCH 3

H2N

NH 2


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diaminopyrimidines inhibitors of dihydrofolate reductase

have activity in both bacterial and protozoal organisms more effective if used in combination with another drug

pyrimethamine is more selective for protozoal enzyme thantrimethoprim

used in treatment of malaria and PCP

PYRIMETHAMINE TRIMETHOPRIM(DARAPRIM)

The fat soluble

vitamins


134/186

By

Henry Wormser

Professor of Medicinal Chemistry

Fat soluble vitamins

Vitamins A D K and E are the fat-


135/186

Vitamins A, D, K and E are the fat-

soluble vitamins excessive use of vitamins A and K can

lead to toxicities fat soluble vitamin tend to be stored in

fatty tissues of the body and in the liver

Vitamin A

Exits in 3 forms:


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Exits in 3 forms:

all trans-retinol long chain fatty acyl ester of retinol (main

storage form)

retinal (the active form in the retina)

retinoic acid is also considered to be

physiologically active provitamin A or carotene can be

converted to retinol in vivo

Vitamin A

recommended intakes are expressed in


137/186

pretinol equivalents (RE)

1 RE = 1 mcg of retinol

= 6 mcg of -carorene= 12 mcg other carotenes

older usage expressed activity in USPunits or International units (IU). Thesewere based on biological activity in the

vitamin a-deficient rat (1 IU = 0.3 mcg ofretinol)

Vitamin A contains 5 conjugated double bonds which are

key to some biological actions

Isolated in impure form by McCollum in 1915


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CH3

CH3H3C

CH3

CH2OH

CH3

VITAMIN A (RETINOL)

RDA: 0.7 mg

Vitamin A

Diseases of deficiency:


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Diseases of deficiency:

Nigh blindness and xerophthalmia (dry eye) Skin disorders

Lack of growth Hypervitaminosis:

A serious potential problem (CNS disorders;

birth defects)

CH3CH3

H3C

CH3

H3C CH3

H3C

CH3CH3

CH3

-caroteneliverO2


140/186

CH3CH3

H3C

CH3

CH3

OH

CH3 CH3

H3C

CH3

CH3

O

H

retinal (active form in vision)

CH3CH3

H3C

CH3

CH3

O

COOH

CH3 CH3H3C

CH3

CH3

retinoic acid ("hormonally-active

form")

R

O

vitamin A acetate (R = CH3)

vitamin A palmitate (R = C16H33

retinol (from diet)

Vision and the role of vitamin A

photoreception is the function of 2


141/186

p p

specialized cell types: rods and cones both types of cells contain a

photosensitive compound called opsin

in rod cells opsin is called scotopsin and thereceptor is called rhodopsin or visual purple

rhodopsin is a serpentine receptor imbeddedin the membrane of the rod cell; it is acomplex between scotopsin and 11-cis retinal


intracellularly, rhodopsin is coupled to a G-


142/186

y, p p

protein called transducin when rhodopsin is exposed to light, it is

bleached releasing the 11-cis-retinal from opsin

absorption of photons by 11-cis-retinal triggersthe conversion to all-trans-retinal (one

important conformational intermediate is

metarhodopsin II); also there is a change in

conformation of the photoreceptor


these transformations activate a


143/186

phosphodiesterase (which hydrolyzes c-GMP toGMP)

c-GMP is necessary to maintain the Na+

channels in the rods in the open conformation

with a decrease in c-GMP, there occurs aclosure of the Na+ channels, which leads to

hyperpolarization of the rod cells withconcomittant propagation of nerve impulses tothe brain


144/186

H3C CH3

CH3

CH3

H3C

N

N

N

O

H

11-cis

Schiff's base


145/186

H H

lysine chain of opsin

CH3H3C

H3C

CH3

N

CH3

N

NO

H

H

H

1. light

2. isomerization of retinal

3. change in shape of rhodopsin

11-trans retinal

signal transduction nerve impulse

RHODOPSIN

(11-cis retinal + opsin)

Additional role of retinol

retinol also functions in the synthesis of


146/186

certain glycoproteins andmucopolysaccharides necessary for

mucous production and normal growth

regulation

this is accomplished by phosphorylation

of retinol to retinyl phosphate which thenfunctions similarly to dolichol phosphate

Retinoic acid (Retin-A) is important for cellular differentiation;

It controls cellular growth particularly cell growth

Used in the treatment of acne; also used as an anti-wrinkle agent

(Retin A, Retin A micro, Avita, Renova)


147/186

CH3

CH3H3CCH3

COOH

CH3

RETINOIC ACID (RETIN A)

Also used orally to treat acute promyelocytic leukemia (APL)

Product used is Vesanoid (10 mg capsules)

Isotretinoin or accutane is a modification of retinoic acid; it

contains a 13-cis double bond and is orally effective

Used in the treatment of severe acne


148/186

CH3

CH3H3CCH3 CH3

COOH

ISOTRETINOIN (ACCUTANE)

CH3 CH3 CH3

COOH

An aromatic analog of retinoic acid; orally effective and

used in the management and treatment of psoriasis


149/186

CH3O CH3

H3CCOOH

ACITRETIN (SORIATANE)

Etretinate (Tegison)

CH CH CH OC H


150/186

CH3

H3C

CH3O CH3

CH3

CH3

O

OC2H

5

Esterified form of acitretin; also used orally in the

treatment of recalcitrant psoriasis; 10 and 25 mg capsules

Alitretinoin (Panretin)

CH


151/186

CH3H3C

CH3

CH3

CO2H

CH3

9-cis-retinoic acid (Alitretinoin)

Currently used as a 0.1% gel for the topical treatment

of cutaneous lesions in patients with AIDS-related

Kaposi sarcoma

BEXAROTENE (Targretin)

CCH2


152/186

CH3

H3CCH3

H3C CH3

COOH

CH2

Bexarotene (Targretin)

indicated for the treatment of cutaneous


153/186

manifestations of cutaneous T-celllymphoma

usually the patients receiving this drug

have failed to respond to other treatment

protocols

pregnancy (Category X drug)

Adapalene (Differin)

HO2CUsed as a 0.1% gel in the

treatment of acne vulgaris


154/186

OCH3

Adapalene

treatment of acne vulgaris

Tazarotene (Tazorac)


155/186

N C C

S

H3C CH3

EtO2C

Topical treatment of patient with facial acne vulgaris of

mild to moderate severity; gel 0.05%, 0.1%

Vitamin A toxicity

vitamin A is higly toxic when taken inlarge amounts either acutely or


156/186

large amounts either acutely orchronically

may occur with 200 mg (666,000 IU) in

adults or half this amount in children signs include headache, nausea andvomiting, increased cerebrospinal fluid

pressure, blurred vision and bulging ofthe fontanelle in infants

Chemical name Abbreviation Generic name

Vitamin D2 D2 ergocalciferol


157/186

Vitamin D3 D3 Cholecalciferol

25-

hydroxyvitamin

D3

25(OH)D3 calciferol

1,25-dihydroxyvitamin D3

1,25-(OH)3 Calcitriol

24,25-dihydroxy

vitamin D3

24,25(OH)2D3 Secalcifediol

Vitamin D

There are 2 major precursor forms: 7-dehydrocholesterol


158/186

7-dehydrocholesterol

ergosterol

UV irradiation affords cholecalciferol (vitamin

D3) and ergocalciferol (vitamin D2) Discovery:

1890 sunlight prevents rickets

1924 Steanbock and Hess found that irradiating certainfoods produced vitamin D2

1970 hormonally active form of vitamin D discovered

Vitamin D

RDA 20 g (required in minute amounts)


159/186

disease of deficiency: rickets Malformation of bones due to improper bone

mineralization

Hypervitaminosis Toxic dose only 10X higher than the RDA

Causes hypercalcemia can lead to cardiac arrest

vitamin D is not a vitamin (or a cofactor) it isa steroid hormone

HO

OH

CH 37-DEHYDROCHOLESTEROL

PRE-D 3


160/186

CH 2

HO

D 3 (CHOLECALCIFEROL)


161/186


162/186

Biological functions

Calcium homeostasis it is critical for the body

to maintain the proper calcium level in the


163/186

to maintain the proper calcium level in the

blood stream

Intestinal calcium absorption: acts as a signal to tell

intestinal cells to take up more calcium from the gut Bone calcium mobilization

Signals osteoclast (bone cells) to release calcium into the

blood stream in response to low calcium levels

Biological functions

Cellular differentiation much less well understood

signal to bone marrow cells to change into other cells


164/186

leukemia cell

1,25(OH)2 vitamin D3

normal white blood cell

derived from bone marrow grows at the proper rate

high levels

Problem: 1,25(OH)2-D3 causes hypercalcemia

Various analogs of vitamin D

Potential use:


165/186

OH

HO

synthetic analog of vitamin D

-anti-cancer agent-immunosuppressive


166/186

CH3

CH3


167/186

CH2

HO OH

H3C

DOXERCALCIFEROL (HECTOROL)

Doxercalciferol (Hectorol)

a synthetic vitamin D analog that undergoes in

vivo metabolic activation to 1-,25-


168/186

dihydroxyvitamin D2

Activation does not require involvement of the

kidneys Used in hyperparathyroidism in patients

undergoing chronic renal dialysis

Initial dose 10 mcg orally 3 times per week

H OH

CH3


169/186

HO

H

OH

PARACALCITOL (ZEMPLAR)

PARICALCITOL (Zemplar)

H OH

CH3


170/186

HO

H

OH

PARACALCITOL (ZEMPLAR)

A synthetic vitamin D analogindicated for the prevention

and treatment of secondary

hyperparathyroidism associated

with chronic renal failure

CH3

H3C OH


171/186

CH2

HO OH

H

CALCIPOTRIENE (DOVONEX)

Calcipotriol (Dovonex)

H3C

OH

a vitamin D derivative approved

f th t t t f i i


172/186

CH2

HO OH

for the treatment of psoriasis.Mechanism of action is unknown.

Receptor affinity is similar to that

of calcitriol, but is less than 1% as

active in regulating calcium

metabolism

Calcipotriene

An analog of vitamin D3 with a modified

id h i t i i 24 OH d


173/186

side-chain containing a 24-OH group anda cyclopropyl group

binds strongly to the D3

receptor on

keratinocytes in skin and it suppresses

their proliferation (used in psoriasis)

has only about 0.5% of the activity of D3on calcium and phosphorus metabolism

Dihydrotachysterol (DHT)

H3CA reduction product of vitamin

D 2


174/186

HO

CH3

D-2Used in the management of

hypoparathyroidism

has only 1/450th the antirachidicactivity of vitamin D-2

Vitamin K

the koagulation vitamin

i t i 2 f


175/186

exists in 2 forms: plant origin: phylloquinone or vit K1 bacterial origin: menaquinones or vit K2

also certain synthetic quinones havevitamin K activity

menadione (vitamin K3) menadiol sodium phosphate (vitamin K4)

O

CH3


176/186

O

CH3

CH3

CH3

CH33

PHYTONADIONE (VITAMIN K 1; PHYLLOQUINONE)

O

CH3


177/186

O

CH3

CH3

CH3

CH3

n = 1 -12

MENAQUINONE (VITAMIN K 2 SERIES)

O

CH3


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O

MENADIONE (VITAMIN K3)

CH2

CO2

CH2 CH2

CHCO

2O

2C

CO2

O2OH

CH3 CH3

O


179/186

3

R

OH

R

O

O

NADH

NAD

WARFARIN & OTHER ANTICOAGULANTS

ANTIVITAMIN K ACTION

OF ORAL ANTICOAGULANTS


180/186

Vitamin E

alpha (E1), beta (E2) and gamma(E3)

tocopherol


181/186

tocopherol sources: plant oils (corn, peanut, wheat

germ), green leafy vegetables, meat, eggs

value resides in the antioxidant

properties of vitamin E (may prevent the

formation of peroxides)

ALPHA TOCOPHEROL


182/186

O

CH3

H3C

HO

CH3

CH3

CH3 CH3

CH3

CH3

ALPHA TOCOPHEROL

Found in a variey of different sources (primarily vegetable fats)

Vitamin E

Estimated requirements: 5 mg/day + 0.6

mg/day of unstaurated fat


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mg/day of unstaurated fat Biological function antioxidant for fatty

acids

Acts like vitamin C; prevents lipid

peroxidation and/or damage to cells by lipid

hydroperoxides

Uses for vitamin E

hemolytic anemia in premature infants,

unresponsive to B12 Fe and folic acid


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unresponsive to B , Fe and folic acid macrocytic megaloblastic anemia seen in

children with severe protein-calorie

malnutrition

Other coenzymesO

O

CH3

CH2CH3O

CH3O

CH C

CH3

CH2 H

10

Serves as entry into the electron-

transport chain


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O

Coenzyme Q (Ubiquinone)

N

N

N

NH2N

H

H OHCHH CH

OH

CH3

OH

Tetrahydrobiopterin

Involved in the conversion ofphenylalanine to tyrosine


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09/12/02

Enzyme Cofactors v1

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