b vitamins 2015 rk part b full slides
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The B-group (part B)
2015
A/Prof Rozanne Kruger
151.232 ~ Nutrition and metabolism151.232 ~ Nutrition and metabolism151.232 ~ Nutrition and metabolism151.232 ~ Nutrition and metabolism
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B-group vitamins learning objectives
Copyright 2005 Wadsworth Group, a division of Thomson Learning
To be able to describe their absorption, transport and
storage
To be able to describe important dietary sources of each vitamin
To be able to discuss the metabolic functions of these vitamins and the consequences of suboptimal and deficient intakes
To know how to assess them in vivo
Relevant pages in Thompson: chapters 8-12
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Vitamin B12 (cobalamin)First recognised for its role in curing pernicious anaemia, which occurred in elderly patients and quickly lead to death.
Vitamin B12 was first isolated from liver in 1948 and the intrinsic factor required for its absorption (a glycoprotein secreted in the stomach) was identified in 1966.
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Vitamin B12 (cobalamin) Closely related to folate
Each depends on the other for activation When folate gives up its methyl group it
activates vit B12 Regeneration of AA methionine (methyl group
donor) and
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Homocysteine
Cystathionine
Cysteine
THF
SAM
5 methyl THF
B12
Methionine
Folate, B12 and homocysteine metabolism
5, 10 methyleneTHF
MS
MS =methionine synthase
DNA
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Vitamin B12 (cobalamin) Closely related to folate
Each depends on the other for activation When folate gives up its methyl group it
activates vit B12 Regeneration of AA methionine (methyl group
donor), and synthesis of DNA+RNA depend both on vit
B12 and Folate Without folate, however, B12 still maintains the
sheath that covers nerve fibers and promotes their normal growth
Bone cell activity and metabolism also depend on vit B12
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Structure of Vitamin B12 Active Vitamin B12 consists of a porphyrin
ring attached to ribose and phosphoric acid.
The porphyrin ring has a cobalt atom in the centre.
The cobalt atom may have either a methyl group or a 5-deoxyadenosyl group bound in active forms of the vitamin.
The synthetic form has a cyanide group.
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Active forms and functions of Vitamin B12
Methylcobalamin: Methionine synthase
(See the methylation cycle)
Deoxyadenosylcobalamin: Methylmalonyl CoA mutase
(Converts methylmalonyl CoA, derived from some amino acids and propionate, to succinate to enter the citric acid cycle.)
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Dietary sources
Second hand Fermentation products from yeast and bacteria (most vegetarians deficient).
Third hand Vitamin B12 is made by microorganisms and assimilated into the food chain through incorporation by herbivorous animals, which are then eaten (or their products, e.g. milk, are eaten) by omnivorous animals.
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Absorption of Vitamin B12 Released from food by action of acid and
pepsin in stomach. Bound by glycoproteins, R binders. R binders broken down in duodenum, then
intrinsic factor (IF) (glycoprotein secreted by parietal cells in stomach) binds B12.
(IF-B12) complex absorbed by ileum.
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Limitation on absorption Vit B12 + IF travels to end of small
intestine where specific receptors recognize the complex (only bound, not alone).
Uptake is limited by the capacity of the ileal uptake system, which is saturated by amounts of about 1.5-2.0 g of B12 in a meal.
During absorption B12 is bound to its transport protein, transcobalamin II (TCII).
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Conservation of B12 Little B12 is excreted in urine as it is so well
bound to transport proteins, TC I, II and III in plasma.
About 1 mg daily is secreted in bile, but is almost all reabsorbed associated with IF enterohepatic circulation
Lack of gastric secretion, and hence lack of IF, causes loss of this B12 as well as that from dietary malabsorption this leads to pernicious anaemia - fatal if not treated.
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Deficiency of Vitamin B12 Megaloblastic anaemia morphologically
indistinguishable from that seen in folate deficiency B12 deficiency causes a build up of cellular 5-methyl
H4PteGlu and reduction of available 5-methylene H4PteGlu. Trapping of folate in this form results in lack of folate
coenzymes for thymidylate and purine synthesis -affects DNA synthesis.
Neuropathy sub-acute combined degeneration of the spinal chord. Creeping paralysis. Irreversible in final stage. Not seen in folate deficiency (with sufficient folate, the
symptoms may develop without evidence of anaemia masking (cures the blood symptoms)
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Copyright 2005 Wadsworth Group, a division of Thomson Learning
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Vitamin B12 Deficiency of folate or B12 produces (due to
folate lack) pernicious anemia
Copyright 2005 Wadsworth Group, a division of Thomson Learning
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Macrocytic and microcytic anemia
Macrocytic anemia: Red blood cells enlarged. Folate and vitamin B12 deficiencies lead to
megaloblastic anemia where red blood cells are enlarged due to abnormal DNA synthesis (unripe / immature rbc).
Microcytic anemia: Red blood cells small. Vitamin B6 or iron deficiency lead to reduced haeme
synthesis and hence small red cells (mature rbc).
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Causes of Deficiency Inadequate dietary intake (rare)
Vitamin B12 is in foods of animal origin, hence vegetarians and vegans are at risk.
Intestinal malabsorption (most common) Pernicious anemia, parietal cells, destroyed by
autoimmune response, do not secrete IF or HCL.
Loss of HCL producing cells from disease e.g. Helicobacter pylori / stomach resection
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Causes of deficiency continued Pancreatic insufficiency
Destruction of R-binders by pancreatic enzymes is essential for absorption.
Drug Interactions Alcohol, colchicine, neomycin and p-
aminosalicylate cause malabsorption. Drugs such as cimetidine, ranitidine,
omeprazole may decrease absorption by lowering gastric secretions.
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Assessment methods Measurement of Transcobalamin 1 in the
plasma Competitive binding to IF in radiometric assays In B12 deficiency methylmalonyl CoA
accumulates is not converted to succinyl CoA, and is broken down to MMA for excretion; hence MMA increases when mutase activity is low; requires a mass spectrometer for the assay
Homocysteine elevation also increased in folate and B6 deficiency.
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Recommended daily allowancesRDI for B12 - 2.4 g/day.
Pregnancy 2.6 g/dayLactation 2.6 g/day
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Therapeutic Uses People having a diet very low in animal products
should use oral vitamin B12 supplement. Those with malabsorption syndromes (atrophic
gastritis), e.g. pernicious anaemia, are usually treated with intra-muscular injections of 100-1000 g of B12 every 1-2 months.
Very high doses do not appear to be toxic, but serve no purpose except in treating malabsorption syndromes.
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Folate (Folic Acid)Pteroylglutamic acid (PGA)
Lucy Wills 1933 - type of macrocytic anemia that occurred in poor pregnant women in India was similar to the pernicious anemia that occurred in elderly subjects.
The elderly would die if not treated, but pregnant women recovered after giving birth.
A similar anemia induced in rats and monkeys by a diet deficient in proteins and vegetables could be cured by MARMITE (and so could her patients).
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Leafy dark green Leafy dark green Leafy dark green Leafy dark green
vegetables (such as vegetables (such as vegetables (such as vegetables (such as
spinach and broccoli), spinach and broccoli), spinach and broccoli), spinach and broccoli),
legumes (such as black legumes (such as black legumes (such as black legumes (such as black
beans, kidney beans, beans, kidney beans, beans, kidney beans, beans, kidney beans,
and blackand blackand blackand black----eyed peas), eyed peas), eyed peas), eyed peas),
liver, andliver, andliver, andliver, and
some fruits (notably some fruits (notably some fruits (notably some fruits (notably
citrus fruits and juices) citrus fruits and juices) citrus fruits and juices) citrus fruits and juices)
are naturally rich in are naturally rich in are naturally rich in are naturally rich in
folate.folate.folate.folate.
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NB USA has mandatory f.a. fortification of all flour products
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Folate
Generic term for compounds with common vitamin activity synthetic folic acid
(pteroyl monoglutamic acid) natural food folates
(pteroyl polyglutamates)
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Structure of folic acid
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Folic acid and THF structures
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Absorption Polyglutamate in food hydrolysed by brush
border enzymes monoglutamate form before uptake by intestinal cells by a saturatable carrier mediated process.
Half of natural folates are 5-methyltetrahydrofolate, the rest are converted to this form in intestinal cells after uptake.
5-methyltetrahydrofolate monoglutamate is therefore the main form in plasma.
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Folate
Copyright 2005 Wadsworth Group, a division of Thomson Learning
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Elongation of the glutamate chain The methylated monoglutamate form of
tetrahydrofolate can have further glutamate residues added in an unusual - linkage to form 5-Methyl tetrahydrofolylpoly- -glutamate
h4PteGlu(n) The polyglutamate forms are generally the most
effective substrates for folate-dependent enzymes, showing increased affinities, and are also retained better in cells.
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Uptake into cells 5-methyltetrahydrofolate monoglutamate enters
cells by diffusion, and is retained by conversion to polyglumate forms
after demethylation via the vitamin B12 dependent methionine synthase.
If polyglutamate forms are already present at high levels, little of the monoglutamate form is demethylated and retained.
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Homocysteine
Cystathionine
Cysteine
THF
SAM
5 methyl THF
B12
Methionine
Folate and homocysteine metabolism
5, 10 methyleneTHF
MS
MS =methionine synthase
DNA
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Cellular folate retention is therefore regulated by:
Cellular folate concentration Plasma folate concentration Vitamin B12 status
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Biosynthetic reactions using 1-carbon units.
One-carbon units are transferred by folates in biosynthetic reactions, e.g.: Pyrimidine synthesis Purine biosynthesis Conversion of homocysteine to methionine
Methionine acts as a source of methyl groups in a wide range of methylation reactions.
Part of coenzymes THF (tetrahydrofolate) and DHF (dihydrofolate) used in DNA synthesis and therefore important in new cell formation
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Catabolism and Excretion Breakdown products are pteridines and p-
aminobenzoylglutamate These are further catabolised before
excretion. Very little intact folate is excreted, so
catabolism is the main factor determining folate requirement.
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Folate deficiencyDeficiency leads to: Megaloblastic anemia (large red cells). Neural tube defects (NTDs) during fetal
developments e.g. spinal bifida Possibly to elevated risk of cancer and
heart disease and to mental abnormalities.
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Figure 15-6Page 512
Spina Bifida
Spina Bifida Normal Spine
Vertebra
Meninges
Spinal cord
Spinal fluid
Spine Spine
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Mega = large Macrocytic
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Folate deficiency Other deficiency symptoms
Smooth, red tongue Mental confusion, weakness, fatigue, irritability, headache
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Causes of deficiency
Low dietary intake Reduced intestinal absorption (sprue and
coeliac disease) Pregnancy due to increased folate catabolism Anticonvulsant drugs; some lipid lowering drugs High alcohol intake leading to decreased
absorption, increased catabolism, often accompanied by poor diet.
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Assessment of folate status Most widely used method:
Measurement of folate in plasma or serum. Better method:
Measurement of red cell folate (more steady). Another method:
Elevation of plasma homocysteine; occurs with even marginal deficiency, but also found
with B12 deficiency need to exclude this.
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Dietary Sources Folate is widely distributed in foods. Best natural dietary source is liver. Difficult to achieve high intakes needed to
prevent NTDs during pregnancy. Fresh vegetables good (folate in foliage),
but need a lot more than is included in most diets.
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RequirementsRDI 400 g/day.
Pregnancy 600 g/dayLactation - 500 g/day
Bioavailability ranges from 50%(food) -100% (supplements on empty stomach)Supplements 1.7x more available than food)
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Mandatory fortification in USA To reduce the incidence of NTD in USA Mandatory f.a. fortification from 1 Jan 1998
140g/100g cereal product Dietary Folate Equivalents (DFE) introduced to
account for differences in bioavailability of natural and synthetic forms 1 units DFE synthetic f.a.= 1.7 units natural folate Units of folate are reported as g DFE
100g food + 100g supplement = 270 DFE (dietary folate equivalents)
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Therapeutic uses, possible toxicity Deficiency usually treated with supplements of
about 5 mg per day for days or weeks. Supplementation in a high-risk pregnancy can
be at 4mg a day. Normal pregnancy 600 g/day is recommended,
and supplements should be taken peri-conceptionally if possible [800 g/day 4 weeks prior to conception & 1st 3 months of pregnancy]
BUT there may be risks with high intakes of folate.
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Possible toxicity High folate intake, particularly with the
synthetic form, folic acid, used in supplements, may: Mask accompanying B12 deficiency, due to
correction of anemia, without correcting neurological symptoms
De-stablise epilepsy. Accelerate growth of some tumours.