vit 1 summary
DESCRIPTION
مراجعة الفيتاميناتTRANSCRIPT
VITAMINS محمد التريكي. د
كيمياء حيوية
جامعة طرابلس –كلية الطب
2013
VITAMIN A
1. Retinoids (animal source as retinyl ester):
a) retinol
b) retinal
c) retinoic acid
(active vit. A ).
2. Carotenoids (plants): mostly α-, β-, and γ-carotenes
and cryptoxanthin (Provit.).
Vitamin A isoforms
Carotenoids → Retinoids in intestinal
mucosa by Carotene Dioxygenase • The intestinal activity of carotene dioxygenase is
low:
- No toxicity of carotenoids.
• The cleavage is of two types:
1. central bond cleavage: → retinal.
2. asymmetric cleavage → retinoic acid.
Retinyl ester (diet)
hydrolysis
FFA
Retinol
Intestinal mucosa
Long chain FA
+ Retinyl ester in
chylomicron
Lymph & circulation
Liver
Stored as retinyl ester
hydrolysis
FFA Retinol
plasma RetinolBinding Protein (RBP)
Peripheral
Tissues
RBP-Receptor
Retinol
Cellular RBP
+
nucleus
ABSORPTION
&
TRANSPORT
OF
VITAMIN A
Function of VITAMIN A
Vision
Reproduction.
Growth.
Maintenance of epithelial tissues
• Retinoic acid mediates all activities, EXCEPT
vision & reproduction (if all vitamin A is given as
retinoic acid → blindness & sreility).
β-carotene acts as an antioxidant.
Vitamin A Has a Function in Vision
• In the retina: all-trans-retinol → 11-cis-retinol → 11-cis-retinal which reacts with opsin, forming rhodopsin.
The absorption of light by rhodopsin causes:
1. isomerization of retinal from 11-cis to all-trans.
2. conformational change in opsin (rhodopsin → → → → → metarhodopsin II → initiates a guanine nucleotide amplification cascade → closes Na+ channels → hyperpolarization → nerve impulse.
3. The final step is hydrolysis to release all-trans-retinal and opsin.
Vitamin A Deficiency
• Signs (in chronological order):
1. Loss of sensitivity to green light (the earliest sign).
2. Impairment of adaptation to dim light.
3. Night blindness.
4. Xerophthalmia (maybe Bitot’s spots).
5. Keratomalacia: corneal ulceration and opacity
(irreversible).
6. blindness.
• increased susceptibility to infections.
Bitots spots
in xerophthalmia
Xerophthalmia
Keratomalacia
HyperVitaminosis A (Vit.A toxicity)
• Symptoms:
CNS: increased CSF pressure: headache, nausea,
ataxia, & anorexia.
Liver: hepatomegaly
Skin: excessive dryness, desquamation, & alopecia.
Calcium homeostasis: thickening of the long bones,
hypercalcemia and calcification of soft tissues.
Pregnancy: congenital fetal malformation.
LDL/HDL ↑
VITAMIN D IS REALLY A
HORMONE
• The most stable vitamin.
• Its Synthesis & activation needs: ski, liver & kidney
• Function: calcium homeostasis.
• It acts as a hormone.
• Deficiency:
1. rickets in children.
2. osteomalacia in adults.
Synthesis of Vitamin D in the Skin
Cholesterol → 7-Dehydrocholesterol
previtamin D → cholecalciferol (Vit. D3) → blood.
In the Liver: 25-hydroxylase → 25 (OH) Vit. D
(=Calcidiol =most abundant form of Vit. D in circulation).
In the kidneys:
- 1α-hydroxylase: (if Ca ↓↓, PTH↑) → 1,25 (OH)2 Vit.D
(=calcitriol=most active form)
- 24-hydroxylase: (if Ca ↑↑) → 24,25 (OH)2 Vit.D (=24-
hydroxycalcidiol = inactive)
UV / no Enz.
Vitamin D Metabolism Both Regulates
& Is Regulated by Calcium Homeostasis
• Calcitriol induces the 24-hydroxylase and inhibits
the 1-hydroxylase in the kidney.
Function:
• to maintain the plasma calcium concentration by:
1. increaseing intestinal absorption of calcium & Pi.
2. stimulating reabsorption of calcium & Pi.
3. mobilizes bone calcium.
• In its actions, it behaves like a steroid hormone.
Vitamin D Deficiency
• Rickets: (children & adolescents). Causes
include:
Dietary deficiency.
Renal rickets: due to renal failure.
Hypoparathyroidism.
• Osteomalacia (adults).
HyperVitaminosis D
• Vitamin D is the most toxic of all vitamins.
Loss of appetite, nausea, thirst.
high blood pressure.
Calcinosis.
Food Sources of Vitamin E
Plant source is more important than animal source.
Vitamin E requirement increases as the intake of polyunsaturated fatty acid increases.
Vitamin C decreases requirement of vitamin E.
VITAMIN E DOES NOT HAVE A
PRECISELY DEFINED METABOLIC
FUNCTION • Vitamin E include tocopherols & tocotrienols.
• The most active is D-α-tocopherol.
• It acts as lipid-soluble antioxidant in cell membranes & lipoproteins.
• deficiency:
1. neurologic disorders.
2. Hemolytic anemia of the newborn.
3. High dose of vitamin E acts as a prooxidant.
VITAMIN K IS REQUIRED FOR
SYNTHESIS OF BLOOD-CLOTTING
PROTEINS Three compounds have the biologic activity of
vitamin K:
1. K1, phylloquinone, from diet.
2. K2, menaquinones, synthesized by intestinal
bacteria.
3. K3: synthetic, water soluble.
Vit. K Function
& Inhibition
Mechanism of action & activation of Vit K
• Vitamin K is the cofactor for the carboxylation of
glutamate residues in factor II, VII, IX, X, protein C
& S, osteocalcin & bone matrix Gla protein.
• Synthesis & activation of Osteocalcin meed vitamins
D, K, &C.
• Vitamin K epoxide is reduced back by epoxide
reductase which is inhibited by Warfarin (dicumarol).
• Deficiency of vitamin K:
1. Newborns.
2. Some antibiotics.
VITAMINS (water-soluble)
محمد التريكي. د
كيمياء حيوية
جامعة طرابلس –كلية الطب
2013
VITAMIN B1 (THIAMIN)
• The active form is (TPP).
• Rxs:
1. Oxidative decarboxylation:
a) pyruvate dehydrogenase
b) α-ketoglutarate dehydrogenase
c) the branched-chain keto-acid dehydrogenase
2. Group transfer: transketolase, in the pentose
phosphate pathway
Thiamin Deficiency Affects
the Nervous System & Heart
• Thiamin deficiency can result in three distinct
syndromes:
1. Dry beriberi: CNS.
2. Wet beriberi: CVS.
3. Wernicke’s encephalopathy & Korsakoff’s
psychosis.
• life-threatening lactic acidosis.
• Thiamin Nutritional Status Can Be Assessed by
RBC Transketolase Activation
VITAMIN B2 (RIBOFLAVIN)
• Active form: FMN & FAD.
• Function: electron transfer in oxidation-reduction reactions.
• deficiency:
1. Cheilosis.
2. lingual desquamation.
3. seborrheic dermatitis.
• Riboflavin nutritional status is assessed by measurement of the activation of erythrocyte glutathione reductase by FAD added in vitro.
NIACIN IS NOT STRICTLY
A VITAMIN
• It is not strictly a vitamin since it can be
synthesized in the body from the essential amino
acid tryptophan.
• Two vitamers: nicotinic acid and nicotinamide.
• Active form: coenzymes NAD and NADP.
• Function:
1. oxidation-reduction reactions.
2. source of ADP-ribose for the ADP-ribosylation
of proteins
Pellagra Is Caused by Deficiency
of Tryptophan & Niacin
• Pellagra is characterized by a photosensitive dermatitis. As the condition progresses, there is dementia, possibly diarrhea, and, if untreated, death.
• Etiology (causes) of pellagra:
1. dietary deficiency of niacin.
2. Dietary deficiency of Trp.
3. Hartnup disease: deficiency of Trp transporter→absorption.
4. Carcinoid tumor.
5. deficiency of vitamin B2 or B6 (required for synthesis of nicotinamide from Trp).
VITAMIN B6
• 6 vitamers: pyridoxine, pyridoxal, pyridoxamine, & their 5′ phosphates.
• The active form (coenzyme) is pyridoxal 5′-phosphate.
• Function:
1. AA metabolism: transamination and decarboxylation.
2. glycogen phosphorylase.
3. Termination of steroid hormone action.
• Vitamin B6 Status Is Assessed by Assaying Erythrocyte Aminotransferases.
• Toxicity: sensory neuropathy.
VITAMIN B12
• Cobalamins: (cobalt containing compounds
possessing the corrin ring)
• Vitamin B12 is found only in foods of animal
origin (no plant source)→Strict vegetarians
(vegans) are at risk of developing B12
deficiency.
Vitamin B12 Absorption • Mouth: Cobalophillin is secreted in the saliva. Vit. B12 is bound to
food.
• Stomach:
HCl & pepsin release the vitamin from protein binding in food and make it available to bind to cobalophilin.
the gastric parietal cells secrete intrinsic factor (IF), a small glycoprotein.
• Duodenum:
cobalophilin is hydrolyzed by pancreatic enz., releasing vitamin for binding to IF.
Pancreatic insufficiency can therefore be a factor in the development of vit. B12 deficiency, resulting in the excretion of cobalophilin-bound vit. B12.
IF binds the various vit. B12 vitamers, but not other corrinoids.
• Terminal ilium: Vitamin B12 is absorbed from the distal third of the ileum via receptors that bind the intrinsic factor-vit. B12 complex but not free IF or free vitamin.
There Are Three Vitamin B12-
Dependent Enzymes
• Vitamin B12-dependent enzymes:
1. leucine aminomutase.
2. methionine synthase: with folic acid.
3. Methylmalonyl CoA mutase.
• urinary excretion of methylmalonic acid provides
a means of assessing vitamin B12 nutritional
status.
Vitamin B12 Deficiency Causes
Pernicious Anemia
• Pernicious anemia: megaloplastic anemia due to vitamin B12 deficiency (functional folate deficiency=folate trap).
• The commonest cause of pernicious anemia is 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.
Tetrahydrofolate Is a Carrier
of One-Carbon Units
• The active form is tetrahydrofolate (THF).
• 5-Formyl-tetrahydrofolate is more stable than
folate (known as folinic acid).
• The major point of entry for one-carbon fragments
into substituted folates is methylene
tetrahydrofolate.
• Serine is the most important source of substituted
folates for biosynthetic reactions.
Inhibitors of Folate Metabolism Provide Cancer
Chemotherapy & Antibacterial & Antimalarial
Drugs
• The methylation of uracil in (dUMP) to (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA.
• The one-carbon fragment of methylene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase.
• Thymidylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division.
• Methotrexate (anticancer), trimethoprim antibiotic, pyrimethamine (antimalarial drugs) are inhibitors of dihydrofolate reductase.
Vitamin B12 Deficiency Causes Functional
Folate Deficiency—the Folate Trap
• 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 vit. B12.
Deficiency of Folic Acid
• Megaloplastic anemia.
• Neural Tube Defects.
• Hyperhomocysteinemia (or homocystinuria): this
leads to atherosclerosis, & hypertension.
BIOTIN
• Source: widely distributed in many foods as biocytin (ε-amino-biotinyl lysine), which is released on proteolysis.
• It is synthesized by intestinal flora in excess of requirements.
• Deficiency:
1. people maintained for many months on parenteral nutrition.
2. people eat abnormally large amounts of uncooked egg white, which contains avidin.
Biotin Is a Coenzyme of Carboxylase
Enzymes
• Biotin functions as a coenzyme in carboxylation reactions.
• Carboxylases use biotin are:
1. acetyl-CoA carboxylase.
2. pyruvate carboxylase.
3. propionyl- CoA carboxylase.
4. methylcrotonyl-CoA carboxylase.
• Biotin also has a role in regulation of the cell cycle, acting to biotinylate key nuclear proteins.
AS PART OF CoA & ACP, PANTOTHENIC
ACID ACTS AS A CARRIER OF ACYL
RADICALS • Function: acyl group metabolism.
• Active form: coenzyme A or acyl carrier protein (ACP).
• The pantetheine moiety is formed after combination of pantothenate with cysteine, which provides the SH prosthetic group of CoA and ACP.
• CoA: in the citric acid cycle, fatty acid synthesis and oxidation, acetylations, and cholesterol synthesis.
• ACP participates in fatty acid synthesis.
Function of Vitamin C 1- It ↑ the activity of a number of enzymes in vitro by a nonspecific reducing action.
2- nonenzymic effects as a reducing agent & antioxidant.
3- absorption of iron.
4- Coenzyme in two groups of hydroxylases:
A) the copper-containing hydroxylases : 1) peptidylglycine hydroxylase.
2) Dopamine β-hydroxylase.
B) Iron-containing hydroxylases: 1. the α-ketoglutarate-linked iron-containing hydroxylases.
2. p-hydroxyphenylpyruvate hydroxylase & homogentisate dioxygenase : in tyrosine degradation.
3. Proline and lysine hydroxylases: procollagen → collagen.
4. proline hydroxylas: for osteocalcin & the C1q component of complement.
5. Aspartate β-hydroxylase: protein C, the vitamin K-dependent protease.
6. Trimethyllysine and γ-butyrobetaine hydroxylases: synthesis of carnitine.
• Vitamers: ascorbic acid & dehydroascorbic
acid
• Vitamin C Deficiency = Scurvy:
1. skin changes.
2. fragility of blood capillaries.
3. gum decay.
4. tooth loss.
5. bone fracture.