VITAMINS

SYNONYMS, VITAMERS
STRUCTURE(S)
SOURCES
PROPERTIES
METABOLISM
-SYNTHETIC COMPOUNDS
-PRO-VITAMINS
-BIOSYNTHESIS (HUMAN)
-STORAGE

BIOCHEMICAL FUNCTIONS
DEFICIENCY MANIFESTATIONS
DIETARY REQUIREMENTS, RDA
ANTI VITAMINS
TOXICITY MANIFESTATIONS
ROLE IN OTHER DISEASES

Vitamin B1 (Thiamine)

A pyrimidyl – substituted thiazole
Active form – thiamine pyrophosphate

Dietary Sources: Unrefined cereal grains, liver, heart, kidney and pork, enrichment of flour.

RDA – 1.5 mg/day

Absorption of B-1

in duodenum

active transport (low thiamin levels)
requires sodium and folic acid

passive transport (hi B-1 levels)

phosphorylation to active form inside cells (TPP)

transported via portal blood

no significant storage, excess to urine

Functions Vitamin B1 (Thiamine)

Ethanol fermentation

Functions Vitamin B1 (Thiamine)

Synthesis of Acetyl CoA

Thiamine deficiency can be caused by-

► Malnutrition -Poor intake e.g. non-enriched rice and wheat.
► Thiaminase (destroy vitamin) present in raw fish, anti-thiamine factors (tea,coffee, betel nuts)
► Chronic alcoholism.

DEFICIENCY MANIFESTATIONS

beriberi.

Wernicke-Korskoff syndrome
Almost exclusively described in chronic alcoholics due to their poor dietetic lifestyles

ROLE IN METABOLISM AS THE COENZYMES FLAVIN MONONUCLEOTIDE (FMN) AND FLAVIN ADENINE DINUCLEOTIDE (FAD)

FMN is formed by ATP-dependent phosphorylation of riboflavin

Flavin Coenzymes Are Electron Carriers in Oxidoreduction Reactions

The hydrogens of FADH2 are on nitrogens 1 and 5 as indicated in the figure.

DIETARY SOURCES

Milk, green vegetables
Yeast, enriched foods
Liver, meats, fish, eggs

RDA: 0.6 mg/1000 kcal
Adults 1.2-1.7 mg/d
Infants 0.4 mg/d

BIOCHEMICAL FUNCTIONS

FMN dependent Enzymes:
ETC - complex I [NADH dhydrogenase]:
e- transport from NAD → FMN →CoQ
Amino acid oxidation
[L-a.a.(FMN is reduced to FMNH2)→L-imino acid →Keto acid]

FAD dependent Enzymes:
TCA: Succinate →Fumarate by Succinate dehydrogenase

Xanthine to uric acid by Xanthine oxidase

Dihydrolipoate dehydrogenase reaction:
a. Pyruvate →acetyl coA

DEFICIENCY MANIFESTATIONS Vit. B2

-Angular stomatitis
-Cheilosis
-Glossitis
-Seborrheic dermatitis
-Photophobia

-Flavins – stable to heat but decomposed by light.
-This characteristic can lead to riboflavin deficiencies in newborns treated for hyperbilirubinemia by phototherapy.

NIACIN (Vitamin B3)

Niacin was discovered as a nutrient during studies of pellagra.

It is not strictly a vitamin since it can be synthesized in the body from the essential amino acid

Two compounds, nicotinic acid and nicotinamide, have the biologic activity of niacin;

NIACIN

its metabolic function is as the nicotinamide ring of the coenzymes NAD and NADP in oxidation-reduction reactions

Dietary sources:
Meats (liver), milk, fish, whole-grain, nuts

RDA: 17-20 niacin equivalents (NE)
per day mg/d

60 mg of tryptophan are required to synthesize 1 mg of niacin

One NE is equivalent to 1 mg of free niacin.

NAD+ Dependent Enzymes: e.g.

1. Lactate dehydrogenase [Lactate→pyruvate]
2. Pyruvate dehydrogenase [pyruvate →acetyl coA]
3. Glyceraldehyde 3-Phosphate dehydrogenase
[Gld 3-P →1,3 BPG]
NADH produced= oxidized in ETC

NADP+ Dependent Enzymes: NADPH generating reactions e.g.

1. G6PD [HMP shunt]
2. Malic enzyme [malate →pyruvate]
3. Isocitrate dehydrogenase

DEFICIENCY MANIFESTATIONS NIACIN

- Pellagra: The severe symptoms,
dementia, dermatitis and diarrhea

Several physiological conditions e.g.
- Hartnup disease- tryptophan absorption is impaired
- Malignant carcinoid syndrome - tryptophan metabolism is altered resulting in excess serotonin synthesis.

BIOTIN

Synthesized by intestinal microorganisms.
Excreted 2 to 5 times more than taken.

- Biotin is bound covalently to the enzyme as a prosthetic group via an
ε-amino group of a lysine residue in the enzyme

- This biotin-lysine conjugated amino acid is termed a "biocytin" residue: coenzyme (form) of biotin

- The lysine side-chain acts as a flexible "tether" for the biotin, and this flexibility allows the transfer of carboxylate groups within the enzyme

Dietary Sources:
Liver, kidneys, vegetables and egg yolk.

RDA: 0.03-0.1mg/d

COENZYME IN CARBOXYLATION REACTIONS
- Acetyl CoA carboxylase (acetyl CoA–malonyl CoA)

- 3-Methylcrotonyl CoA carboxylase (methylcrotonyl CoA – methylglutaconyl CoA in degradative pathway of leucine)

- Propionyl CoA carboxylase (propionyl CoA – 5-methylmalonyl CoA)

- Pyruvate carboxylase (pyruvate – oxaloacetate)

DEFICIENCY MANIFESTATIONS BIOTIN

Seborrheic dermatitis, anorexia, nausea, muscle pain.

- drugs that inhibit growth of intestinal bacterial, e.g. antibiotics and sulphonamides.

- Avidin of raw egg white inhibits biotin absorption.

PANTOTHENIC ACID

- also known as vitamin B5.
- formed from β-alanine and pantoic acid
- Cysteine provides the SH prosthetic group of CoA and ACP
- coenzyme A or CoA: central role in all metabolisms

PANTOTHENIC ACID

Acyl carrier protein (ACP) domain of fatty acid synthase.
participates in fatty acid synthesis

At least 70 enzymes have been identified as requiring CoA or ACP derivatives for their function.
Eg.
-Pyruvate dehydrogenase
-alfa-Ketoglutarate dehydrogenase

Dietary sources:
Egg yolk, liver, kidney, milk, broccoli
-RDA: 5-10 mg/day
-Deficiency – practically unknown

Dietary source
Animal products (liver)
Leafy green vegetables
Easily destroyed by cooking

RDA: 0.2-0.4 mg/d
Pregnancy/lactation 0.5-0.8 mg/d

Digestion & Absorption

dietary form: polyglutamyl folate
glutamate gamma linked
(The folates in foods may have up to seven additional glutamate residues linked by γ-peptide bonds.)
-folate absorbed as monoglutamate (free folate)
-dietary supplement: free folate

Folate Functions

Interconversion of serine and glycine

Degradation of histidine
his->->formiminoglutamate
(FIGLU)

histidine load test
Functional test for folate status

Conversion of Homocysteine to Methionine

Impairment of methionine synthase in B12 deficiency results in the accumulation of methyl-tetrahydrofolate—the “folate trap.” There is therefore functional deficiency of folate
secondary to the
deficiency of vitamin B12.

Deficiency:

most common vitamin def. esp. pregnancy
Due to:
gut sterlization, poor intake and intestinal
absorption, excessive demand,
antifolate e.g. methotrexate, anticonvulsant phenytoin

- Affects cells that are dividing rapidly because
they have a large requirement for thymidine for
DNA synthesis. Clinically, this affects the bone marrow, leading to megaloblastic anemia.

- Neural tube defect particularly in first weeks of
fetal life.

Vitamin B-12

Cobalamine
R may be varied to give the various forms of the vitamin, eg,
R = CN– in cyanocobalamin;
R = OH– in hydroxocobalamin;
R = 5′-deoxyadenosyl in
5′-deoxyadenosylcobalamin;
R = H2O in aquocobalamin; and
R = CH3 in methylcobalamin

methyl cobalamine
- transport and coenzyme form
adenosyl cobalamine
- storage and coenzyme form.

Dietary Sources

Animal products
- including milk and eggs
GI microorganisms
Vegan sources
- N-fixing legumes
- fortified grains
- vitamin supplements

RDA: 4-5 µg/d
Total body stores: 2-5 mg (½ stored in the liver)

Digestion & Absorption of B-12

Dietary intake

Acid-pepsin in the stomach
Gastric acid and pepsin release the vitamin from protein binding in food and make it available to bind to cobalophilin (R), a binding protein secreted in the saliva

Secretion of IF by gastric parietal cells

Pancreatic proteases hydrolyze cobalophilin releasing the vitamin for binding to intrinsic factor.
Pancreatic insufficiency can therefore be a factor in the development of vitamin B12 deficiency, resulting in the excretion of cobalophilin-bound vitamin B12.

Absorbed from ileum via receptors that bind the intrinsic factor-vitamin B12 complex but not free intrinsic factor or free vitamin.

Functions of B12

Homocysteine to Methionine: methionine synthetase
- requires 5-methyl THF
- deficiency of B12 results in “folate trap” results in megaloblastic anemia: synergistic effect of B12 and folate
Mutases
- methyl malonyl CoA mutase
- leucine aminomutase

Causes of B-12 Deficiency

-Inadequate intake - rare
-Malabsorption of B-12
-IF deficiency
-other GI tract problems

Vitamin B12 Deficiency

Pernicious Anemia
The classic description of patient with PA
- Lemon colored skin (anemia/icterus)
- Shiny tongue (atrophic glossitis)
- Mentally sluggish
- Shuffling broad gait

arises when deficiency blocks the metabolism of folic acid, leading to functional folate deficiency.

This impairs erythropoiesis, causing immature precursors of erythrocytes to be released into the circulation (megaloblastic anemia).

The commonest cause - failure of the absorption of vitamin B12 rather than dietary deficiency.

This can be due to failure of intrinsic factor secretion caused by autoimmune disease of parietal cells or to generation of anti-intrinsic factor antibodies.

PYRIDOXINE (B6)

Natural forms: pyridoxine (pyridoxol), pyridoxamine and pyridoxal

Each vitamer can be phosphorylated → pyridoxal phosphate (PLP)

Biologically active form of vitamin B6 is pyridoxal-5-phosphate (PLP)

Dietary sources:Liver, fish, nuts and whole grain cereals.

RDA – 1.8 mg/day.
preg, lact=2.5 mg/day

PLP act as coenzyme for many reactions in amino acid metabolism

Reactions involving PLP as coenzyme:
1. All transaminases (aminotransferases)
[PLP + Amino acid →Schiff base →Keto acid (→enter TCA →energy)]
2. Serine-threonine dehydratase
3. Amino acid decarboxylation (Histidine → Histamine; Glutamate →GABA; 5-Hydroxy tryptophan → Serotonin; Tyrosine →Dopamine, epinephrine , norepinephrine)
4. Cystathionase (cystathionine →Homoserine + cysteine)
5. Cystathionine synthetase
(homocysteine + serine → cystathione)
6. Serine transhydroxymethylase (serine – glycine)
7. Glycogen phosphorylase (glycogenolysis)
8. 5-Aminolevulinate synthetase (RLS in heme synthesis)

Deficiency:

Neurological dysfunction: depression, irritability, nervousness, confusion, severe-convulsions and peripheral neuropathy
[due to ↓ed synth of biogenic amines - serotonin, GABA, norepi,epinephrine]

Anemia: due to decreased heme synthesis

INH [ATT] combine with B6  Inactive Pyridoxal phosphate: long term use in TB patient-peripheral neuropathy so vit B 6 supplement required with INH.

Toxicity:dose >100mg-numbness, muscle weakness, imbalance, nerve damage

Vitamin C - ASCORBIC ACID

Both Ascorbic acid and dehydroascobic acid have vitaminic activity

Vitamin C ASCORBIC ACID

Dietary source:
Citrus fruit
Fresh fruit
Vegetables

Absorption: distal small intestine
Intake up to 100 mg/d - 100% absorbed
Intake >1000 mg/d - <50% absorbed

Excess of vit. C removed by kidneys

Functions of Vitamin C

Enhances absorption of iron
reduces iron to more absorbable ferrous form
chelates with ferrous ion to make it more soluble

Hydroxylation of proline and lysine
post-translational reaction of procollagen

Hydroxylation Reactions
- Carnitine synthesis
- Tyrosine synthesis & catabolism

Synthesis of Neurotransmitters
-Dopamine
-Norepinephrine
-Serotonin
Bile acid synthesis -7 a hydroxylase

Antioxidant Activity
Reacts and removes active oxygen species

Pro-oxidant Activity
Reduces metals to their pro-oxidant forms

SCURVY

-Bleeding gums
-easy bruising
-impaired wound healing and bone repair
-joint pain
-anemia