b vitamins 2015 rk part a full slides

7/23/2019 B Vitamins 2015 RK Part a Full Slides

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The B-group (part A)

2015

A/Prof Rozanne Kruger


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B-group vitamins

learning objectives

Copyright 2005 Wadsworth Group, a division of Thomson Learning

To be able to describe important dietary sources of eachvitamin

To be able to discuss the metabolic functions of thesevitamins and the consequences of suboptimal and

deficient intakes


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B vitamins names and functions

Thiamin B1 Metabolism of energy yieldingRiboflavin* B2 intermediates via red/ox reactions

Niacin B3Pyridoxine* B6 TransaminationCobalamin B12 Transmethylation*

Folate B9Pantothenic acid B5 Constituent of coenzyme ABiotin B7 Carboxylation using coenzyme AInositol B8


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Absorption sites


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Pathways involving B-vitamins

PLP = Vit B6NAD/NADP = Niacin (B3)TPP = Thiamin (B1)FMN/FAD = Riboflavin (B2)CoA = Pantothenic acidTHF = Folate

Biotin, Vit B12

A number of the

coenzymes involvedin importantmetabolic pathwaysrequire B vitaminsfor their activity


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Thiamin discovery First discovered as essential through

deficiency symptoms of a condition knownas beriberi, that occurred with use ofpolished rice in late 19th and early 20th

centuries. Thiamin is removed from cereals by

refining, as most of the thiamin is in thehusk of grains.

Polished rice is very low in thiaminHowever, inward diffusion of water soluble

vitamins means that parboiled rice retains

most of its thiamin.


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I cannot, I cannot 1870 Marked increase in

beriberi incidence in SE Asia3

Polished rice

Christiaan Eijkman

White rice can be poisonous!(1896)3

The anti-beriberi factor

Gerrit Grijns

Suggested dietary deficiency

(1901)4


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Thiamin

RDI

men: 1.2 mg/day

women: 1.1 mg/day

NRVS NHMRC 2006


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Thiamin sources hole grains!

"orti"ied! or enrichedgrain products

#oderate amounts inall nutritious "ood

$or%



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Absorption Absorbed by an active saturable process

Mainly from upper intestine

Maximum absorbed from a single dose

2.5mg At intakes >5mg per day a second passive

absorption process operates

Alcohol inhibits the active transportprocess


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Storage and excretion Very little free thiamine stored in the tissues

Most (90%) is present as active co-enzyme,thiamin pyrophosphate (thiamin diphosphate)

10% in brain (thiamin triphosphate) role

unclearCirculates in the blood bound to albumin

Excreted intact in urine, with renalconservation during pregnancy


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Measuring vitamin status functional markersEnzyme activation co-efficients

Method

Obtain blood sample and measure enzymeactivity

Add a known dose of the vitamin coenzyme

Re -measure the enzyme activity again The enzyme function after the addition of thevitamin coenzyme is divided by the pre-additiontest result to give the activation co-efficient

an increase in ETK (erythrocyte transketolase) of >20%is indicative to risk of thiamin deficiency, an increase of15% is considered normal.

ETK-AC > 1.2= deficiency

The ETK-Ac increases with greater deficiency


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Vit B1~ Thiamin

Assists in energy metabolism as a coenzyme -pyrovate acetyl coA (TPP Coenzyme)

Also role on nerve cell membranes


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Functions of Thiamin

Thiamin pyrophosphate (TPP) is the coenzymefor 3 oxidative carboxylation reactions:

Pyruvate dehydrogenase in carbohydrate (CHO)metabolism (required for conversion of pyruvate toacetyl- coenzyme A) (pyruvate & lactate accumulate)

Alpha keto glutarate dehydrogenase in the citric acid

cycle

Branched chain keto acid dehydrogenase involved inamino acid metabolism (leucine, isoleusine, valine)


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Functions of Thiamin

Thiamin pyrophosphate is also the coenzymefor transketolase, in the pentose phosphatepathway of CHO metabolism (alternativepathway of glucose metabolism)

Thiamine triphosphate has a function in nerveconduction


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Causes of deficiency Diets high in polished rice (in W world most

thiamin comes from fortified breads/cereals Malnourished alcoholics have marked reductionsin thiamin

Outbreaks of thiamin deficiency disease are often

seasonal due to a general shortage of foods Some foods contain anti-thiamin factors e.g. shell

fish and ferns (thiaminase)

Breast fed infants are at risk if mother has lowthiamin intake (breast milk is not a good source ofthiamin)


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Deficiency: Beriberi2 major manifestations of thiamin deficiency:

Cardiovascular disease Wet beriberi

Neurological disease Dry beriberi

Symptoms:

Wet beriberi (acute) swelling (oedema), increased heartrate (tachycardia), lung congestion, congestive heartfailure due to accumulation of pyruvate & lactate promptresponse to treatment

Dry beriberi (chronic) pain, tingling or loss of sensation inhands and feet (peripheral neuropathy), muscle wastingwith loss of function of lower extremities (inability to lift foot

= foot drop), absent ankle jerk, brain damage and death.


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Wet beriberi


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Dry beriberi


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Symptoms Vision changes

Double vision

Eye movement abnormalities(nystagmus)

Eyelid drooping

Loss of muscle coordination Unsteady, uncoordinated

walking Loss of memory, can be profound

Inability to form new memories Confabulation (making up stories) Hallucinations

Staggering


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In western word main cause of thiamindeficiency- alcoholism

Wernicke encephalopathy alcohol relatedbrain damage language problems, walkingdifficulty, unusual eye movement

Korsakoff Syndrome (Korsakoffs psychosis) amnesia, inability to learn or retain newmemories, confabulation

Deficiency: Beriberi


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RiboflavinOther names: Vitamin B2 2006 RDI

Men: 1.3 mg/day

Women: 1.1 mg/day

Chief functions in the body Part of coenzymes FMN (flavin

mononucleotide) and FAD (flavin adenine

dinucleotide) used in energy metabolism. Participate in the flavoproteins in the

oxidation chain in the mitochondria


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&ibo"lavin

'ources



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Riboflavin Vitamin B2

Principal dietary sources: Milk products, poultry, meat, fish.

Smaller amounts in vegetables and cereals, but maycontribute a high proportion of requirements if these are

a major part of the diet. Dietary riboflavin occurs as FAD and FMN

protein bound.

Easily destroyed by ultraviolet light, irradiation Opaque containers NOT SEE-THROUGH

Heat stable


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Recommended daily intake for

Riboflavin.

The difference between an intake that isinadequate and may lead to deficiency(0.45-0.55 mg/day) and an intake that will

saturate tissue stores (~1.1 mg/day) isvery small.

This is because the storage capacity isvery limited.


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Absorption of RiboflavinDietary FAD and FMN are released from

protein by stomach acid and hydrolysed tofree riboflavin or FMN bound to albumin inthe upper intestine.

Riboflavin is absorbed by a sodium dependent, saturable process, and

converted to FMN in the intestinal cells.


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Transport, storage and excretion.

Transported bound to albumin.

Stored mainly as FAD, some as FMN, littleas free riboflavin.

Most storage is in liver, also in muscle Excreted in the urine

Some enters the enterohepatic circulation


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Measurement of RiboflavinMeasurement of activity of red cell

glutathione reductase, with and withoutaddition of FAD.

Erythrocyte glutathione reductase activation

co-efficient (EGRAC)

Ratio of activity with FAD of 1.2 or higherindicates a risk of deficiency.


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Riboflavin chief functions Part of coenzymes:

FMN (flavin mononucleotide) and

FAD (flavin adenine dinucleotide)used in energy metabolism - oxidation chain inthe mitochondria (picks up 2 hydrogens from

TCA cycle)


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Riboflavin chief functions

The enzymes that require FMN or FAD ascofactors are termed flavoproteins.

Several flavoproteins also contain metalions and are termed metalloflavoproteins.

Both classes of enzymes are involved in awide range of redox reactions, e.g.

succinate dehydrogenaseand

xanthine oxidase,

NADH dehydrogenase.

&ib "l i


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&ibo"lavin



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FMN and FAD electron acceptors participate ascofactors in many oxidation-reduction reactionse.g. in the catabolism of glucose, fatty acids,ketone bodies and amino acids.

coenzyme that transfers energy from one

compound to another if AA are used for energy, necessary for

deamination

essential for growth and tissue repair If thiamin lacking, riboflavin likely lacking too

Riboflavin chief functions


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Deficiency disease: Ariboflavinosis


Deficiency symptoms

Inflamed eyelids and sensitivity to light,reddening of cornea (photophobia)

Sore throat

Cracks and redness at corners of mouth

(angular stomatitis)(cheilosis)[perlche] Painful, smooth, purplish red

(magenta) tongue (glossitis)

Inflammation characterized by skinlesions covered with greasy scales (seborrhea)

Growth retardation


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Deficiency disease: Ariboflavinosis


Deficiencies

NZ inadequate intakes low but more likely inPacific children or females (11-18yrs; Mori;with food security concerns)

Vegans or others who dont consume animalproducts must ensure ample servings of darkgreen leafy veges

Toxicity symptoms: none reported Highly unlikely in NZ

Gl i i


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Glossitis


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glossitis


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angular stomatitis


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Cheilosis

Capillary infiltration of the cornea Angular palbebritis


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Dyssebacia

sebaceous plugs


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Niacin (Nicotinic Acid)Deficiency disease is called pellagra

(rough skin shark skin / sandpaper). First recognised during the 19th Century in

Europe and Southern USA maize diets,

and in India with millet diets. Animal protein reversed the deficiency

symptoms, and eventually the important

factor in protein was shown to betryptophan.

Niacin


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Niacin


Other names

Nicotinic acid

Nicotinamide Niacinamide

Vitamin B3

Precursor: dietary tryptophan

2006 RDI

Men: 16 mg NE/day Women: 14 mg NE/day

Upper level for adults: 35 mg/day

Niacin


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Niacin


Chief functions in the body

Part of coenzymes NAD (nicotinamide adenine

dinucleotide) and NADP (its phosphate form)used in energy metabolism

Significant sources

Milk, eggs, meat, poultry, fish Whole-grain and enriched breads +cereals

Nuts

All protein-containing foods

Also converted from tryptophan


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(iacin'ources



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Conversion of tryptophan to niacin.Note that vitamin B6 is required for this

process. A high leucine : isoleucine ratio may

reduce tryptophan availability and cause

pellagra, particularly if vitamin B6 is alsolow.

Dietary tryptophan: a source of


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Dietary tryptophan: a source of

niacin For normal adults in nitrogen balance, all

required niacin can be obtained bysynthesis from dietary tryptophan: 60 mg of tryptophan are required to

synthesize 1 mg of niacin

Also, synthesis of niacin from tryptophanrequires vitamins B1, B2 and B6 which wouldbe limiting in themselves on a marginal diet.

EXAMPLE: Protein intake 80 g/day ;Tryptophan ~ 1000 mg (12.6 mg/g protein) ;Yields ~ 17 mg niacin using the conversion

factor: 60 mg diet. tryptophan = 1 mg niacin.


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Absorption, transport and excretion Nicotinic acid and nicotinamide absorbed by

sodium-dependent saturable transport and bypassive diffusion.

Circulate in plasma, enter tissues by diffusion.

Converted to co-enzyme forms in various tissues

Many catabolites of niacin have been identified,but only two appear in the urine.

Functions


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Functions Niacin is converted to NAD+ and NADP.

Essential for the function of all enzyme-

catalysed reactions that involve NAD+(catabolism) and NADP (anabolism).

Vital for glycolysis, fatty acid metabolism, tissuerespiration, detoxification reactions and many

other pathways. necessary for getting energy from the macronutrients

synthesis of fatty acids and cholesterol

supports health of skin

nervous system

digestive system


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1900s pellagra caused 87000 deaths due to lowprotein diet with high corn content

HOW?

low protein diet / high corn diet high leucine incorn interferes with tryptophane absorptionB3 in Corn too complex to absorb (niacytin)

bound to complex CHO & small peptides


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Deficiency: Pellagra

Pellagra - the 4 Ds (black tongue in dogs)

Dermatitis is most characteristic, and occurs inskin areas exposed to sunlight.

Diarrhoea not always seen.

Dementia - mental changes may includeconfusion, loss of memory, disorientation andvarious psychoses.

Death

Mouth signs similar to riboflavin deficiency.


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Deficiency: Pellagra

PellagraPellis=skinA h


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Agra=rough

Diarrhoea

D i i *


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Dermatitis*

DementiaDeath

Skin darkens and flakesBilateral & Symmetrical

Occurs only on parts exposed to sunlight


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Hartnups disease Pellagra is seen in Hartnups disease.

This is a disorder of amino acidabsorption, in which several amino acids,including tryptophan, are poorly absorbed.


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Assessment of niacin deficiency

No satisfactory blood measureMeasurement of urinary metabolites is

used to assess risk of deficiency.

Urinary concentrations of metabolites N-methylnicotinamide and N-methyl-2-pyridone-5-carboxamide are decreasedin deficiency.


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Toxicity symptoms

Painful flush, hives, and rash

(niacin flush)

at intakes>200mg/d

Excessive sweating

Blurred vision

Liver damage, impaired glucosetolerance


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Pharmacological useNicotinic acid is the most effective broad

spectrum lipid drug doses 1-3gReduces total cholesterol and increases

HDL cholesterol concentrations

Decreases circulating free fatty acids byinhibiting lipolysis in adipose tissue

Limitations? possible liver damage and diabetes


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Vitamin B6


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6

Three forms (interconvertible):

Pyridoxine (alcohol form) - plants

Pyridoxal (aldehyde form) - animals Pyridoxamine (amine form) - animals

All three forms can undergo phosphorylation.The active form is pyridoxal phosphate .

2006 RDI Adults (19-50 years): 1.3 mg/day

Upper level for adults: 50 mg/day

)itamin


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B*

'ources


Meats, fish,

poultryPotatoes,legumes, noncitrus fruits

FortifiedcerealsLiverSoy products


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Functions


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Part of coenzymes PLP (pyridoxal phosphate) and PMP(pyridoxamine phosphate) used in amino acid(homocysteine) and CHO metabolism (DNA & RNA)

Fatty acid metabolism formation of essential FA (linoleic acidarachidonic acid) Synthesis & turnover of cholesterol

Main function in protein metabolism transamination anddeamination of proteins

NE amino acids (serotonin, threonine) Synthesis & metabolism of

tryptophan (trpniacin) Methionine to taurine, GABA

Formation of cross-linkages in elastin formation Maintenance of cellular immunity - production of antibodies Helps make RBCs form precursor of porphyrin ring of

haeme (part of haemoglobin)

Functions


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Release glycogen from the liver and muscleas glycogen phosphate.

Forms part of the phosphorilase enzyme(glycogen glc-1-phosphate)(gluconeogenesis)

Form sfingolipids necessary for development

of myelin sheaths in nerve cells CNS metabolism & ability to transmit nerve

impulses (synthesis of neurotransmitters

(serotonin, norepinephrine, taurine,dopamine), tryptophan serotonin)

Physiological roles of PLP-


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dependent enzymes:

Transamination reactions involved inoxidative metabolism of amino acids.

Decarboxylation reactions giving amines.

Glycogen breakdown glycogenphosphorylase.

Synthesis of niacin from tryptophanHaeme synthesis


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Role of B6 in regulation of hormoneaction

Terminates (turns off) hormone action by

releasing hormone receptor complexes

Modulates the actions of the steroidhormones

oestrogens, androgens, progesterone, retinol,

thyroid hormones and calcitriol (active form ofvitamin D)

Absorption, metabolism and


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excretionMost B6 in foods as PLP bound to

enzymes

B6 dephosphorylated before absorption,taken up by diffusion, then re-

phosphorylated for incorporation intoenzymes where required.

PLP not incorporated into enzymes is

dephosphorylated, and oxidised to 4-pyridoxic acid in the liver for excretion.

Deficiency: anaemia


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y

Severe deficiency is rare: leads to seizures,

may produce anaemia lack of haeme. Deficiency may occur with:

malabsorption problems, dialysis for chronic renal failure, chronic alcoholism.

Marginal deficiency may be more common, andmay predispose to atherosclerosis and cancer of

the breast, uterus and prostate. Plasma [B6] tends to decrease with age.

Deficiency


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Neurotransmitters diminish

Abnormal Tryptophan synthesis products

accumulate in brain Symptoms

Depression

Confusion

Abnormal brain wave patterns Convulsion

Alcohol loss of B6

Broken down = acetaldehyde dislodges PLPcoenzyme from enzyme excreted

Oral Contraceptives depletes PLP, howevercontroversy exists


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Dermatitis greasy, flaky skinGlossitis

Microcytic anemia


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Microcytic anemia


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Drugs may cause B6 deficiency


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The following drugs:

Isoniazid (tuberculosis treatment) Penicillamine (rheumatoid arthritis,

Wilsons disease)

Benserazide, carbidopa (Parkinsonsdisease)

Oral contraceptives

May cause B6 depletion, which in turn alsocause niacin (nicotinic acid) depletion.

Assessment of B6 status


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Best methods are: Plasma concentration of PLP

Erythrocyte transaminase activation. ? Methionine load

(incomplete metabolism of methionine can result

in increased homocysteine) Non-specific measure = Tryptophan load tests

If person has deficiency, the aa trp get trappedand the intermediate kynurenine is shunted to

xanthurenic acid rather than niacin (testpresence in urine).


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Requirements for B6


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High protein in diet increases losses, so

requirements are linked to dietary protein. Intakes of 15-16 g/g protein are

recommended.

RNI 1.5 -1.6 mg/day at an average proteinintake of 100 g/day.

Toxicity of B6


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Very high doses (2-7 g/day) may causeneurological damage / problems.

Supplements 200-2000mg have beenused for treating depression, carpal tunnelsyndrome and premenstrual syndrome,but there is little scientific evidence tosupport the effectiveness.

May be toxic. Safe upper limit 100 mg/day.

Pantothenic Acid


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Panthos = everywhere

As a coenzyme takes part in the metabolism of carbohydrates

and fats

It is essential for the oxidation of pyruvic acid

More than 100 steps in synthesis of lipids ,neurotransmitters , steroid hormones andhaemoglobin

Part of Co Enzymes (Coenzyme A!) Present in TCA cycle

Recommendation = 5mg/d adults

Pantothenic Acid


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2006 adequate intake (AI)

Adults: Men: 6 mg/day

Women: 4mg/day

Significant sources Widespread in foods

Organ meats, mushrooms, avocados,

broccoli, whole grains

Easily destroyed by food processing

Pantothenic AcidA di th l d i ti f b t i id hi h i


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A dimethyl derivative of butyric acid which islinked to b-alanine.

Essential component of Coenzyme A (CoA) lipid and CHO metabolism,

fatty acid synthesis,

steroid hormone synthesis,

gluconeogenesis. Key element in energy production (Krebs cycle)

used for

energy release from the macronutrients synthesis of fat

formation of haeme

synthesis of cholesterol and neurotransmitters


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Absorption, metabolism & excretion


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CoA in foods hydrolysed by intestinalphoshatases to produce pantothenic acid.

Absorbed as pantothenic acid, via active

transport through a saturable, sodium-dependent carrier.

CoA is resynthesized in liver cells. Pantothenic acid is excreted in the urine.

Assessment of status


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Pantothenic acid can be measured in urine

and blood microbiologically or radio-immunologically.

Normal blood levels > 100mg/dl

Normal urinary excretion 1-15 mg/day

Urinary values are used as a sensitive

indicator of dietary intake.

Pantothenic Acid


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Deficiency symptoms

Rare observations made from clinicallyinduced states

Vomiting, nausea, stomach cramps

Insomnia, fatigue, depression, irritability,restlessness, apathy

Hypoglycemia, increased sensitivity to insulin

Burning feet syndrome

Toxicity symptoms: none reported

BiotinChief functions in the body


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Chief functions in the body Part of a coenzyme that carries activated carbon

dioxide. The role is critical in the TCA cycle:

biotin delivers a carbon to 3-carbon pyruvate, thus replenishing oxalo-acetate,

the 4-carbon compound needed to combine with

acetyl CoA to keep the TCA cycle turning. Also participates in:

gluconeogenesis,

fatty acid synthesis, and the breakdown of certain fatty acids and amino acids

Recent research had uncovered a role in gene

expression

Dietary sources and availability


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Biotin is present in liver, egg yolk, soy

flour, cereals and yeast. Fruit and meat are poor sources.

Generally plant sources have higher

content than animal sources Availability is governed by binders in food:

in raw egg white, and in wheat biotin ispresent in an unavailable bound form.

Significant sources

Dietary sources and availability


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Significant sources Widespread in foods

Organ meats, egg yolks, soybeans, fish,

whole grains The protein avidin found in raw egg whites

binds biotin and prevents absorption

Avidin is destroyed by heating Also produced by GI bacteria large

intestine (may not contribute much to biotinabsorbed)

2006 adequate intake (AI) very small quantities

Adults: 30 g/day

Digestion and absorption


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Protein-bound biotin in the diet is digested togive: biocytin, biotin with a lysine residue covalently bound, or

biotinyl-lysyl peptides.

These are hydrolysed by a specific enzymecalled biotinidase.

Free biotin is taken up by sodium-dependentactive transport.

Biocytin is only slowly taken up by passivediffusion.

Metabolism and excretion


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Absorbed biotin is

converted to biotinyl-5-adenylate (in areaction with ATP) ;

then incorporated into the apocarboxylase

forms of the four carboxylases for which itserves as a cofactor.

Biotin and metabolites are excreted in

urine at a rate of about 6-50 mg/day.


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Metabolic role of biotin


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The only known metabolic role of biotin isas a coenzyme for 4 carboxylase enzymes: Acetyl CoA carboxylase (fatty acid synthesis)

Pyruvate carboxylase (oxalo-acetate synthesisfor the TCA cycle, gluconeogenesis)

3-methylcrotonyl CoA carboxylase (catabolismof ketogenic aa leucine)

Propionyl CoA carboxylase (catabolism of odd-

chain fatty acids and some amino acids)

Biotin Deficiency


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Human biotin deficiency is rare; occurs

only with: very unusual diets

egg white injury,

incorrect total parenteral nutrition (TPN), severe malnutrition, or

chronic use of some anticonvulsant drugs

(phenytoin, primidone, phenobarbital,carbamazepine).

Biotin Deficiency - symptoms


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Neurological impairment:

Depression, lethargy, hallucinations, numbness or

tingling sensation in the arms and legs

Skin rash (seborrhoeic dermatitis) red scalyrash around the eyes, nose and mouth (due to

altered fatty acid metabolism), glossitis Hair loss (alopecia)

General symptoms include fatigue, nausea,

anorexia, muscle pains, anaemia, and elevatedserum cholesterol (hypercholesterolaemia).


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Assessment of deficiency


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Assay of biotin-dependent carboxylase activity inlymphocytes has been used to monitor biotin

status in malnutrition. Low activity of the carboxylases has been

reported in studies on children with marasmus or

kwashiorkor. Supplementation with biotin increased the

activity of the carboxylases.

Biotin assayed in whole blood or urine bymicrobiological assay (normal whole blood 0.22 0.75 mg /ml)

Summary so farPyrovateB1

(TPP)Biotin


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B2(FAD/FMN)

B3(NAD/NADP)

b vitamins 2015 rk part a full slides

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