Vitamins are organic molecules that
function in a wide variety of capacities within the
body. The most prominent function is as cofactors
for enzymatic reactions. The distinguishing feature
of the vitamins is that they generally cannot be synthesized
by mammalian cells and, therefore, must be supplied
in the diet. The vitamins are of two distinct types:
| Water Soluble Vitamins |
Fat Soluble Vitamins |
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Thiamin
Thiamin is also known as vitamin B1
. Thiamin is derived from a substituted pyrimidine
and a thiazole which are coupled by a methylene bridge.
Thiamin is rapidly converted to its active form, thiamin
pyrophosphate, TPP, in the brain and liver by
a specific enzymes, thiamin diphosphotransferase.
TPP is necessary as a cofactor for the pyruvate
and a-ketoglutarate dehydrogenase catalyzed reactions
as well as the transketolase catalyzed reactions of
the pentose phosphate pathway. A deficiency in thiamin
intake leads to a severely reduced capacity of cells
to generate energy as a result of its role in these
reactions. The dietary requirement for thiamin is proportional
to the caloric intake of the diet and ranges from 1.0
- 1.5 mg/day for normal adults. If the carbohydrate
content of the diet is excessive then an in thiamin
intake will be required.
The earliest symptoms of thiamin deficiency
include constipation, appetite suppression, nausea
as well as mental depression, peripheral neuropathy
and fatigue. Chronic thiamin deficiency leads to more
severe neurological symptoms including ataxia, mental
confusion and loss of eye coordination. Other clinical
symptoms of prolonged thiamin deficiency are related
to cardiovascular and musculature defects. The severe
thiamin deficiency disease known as Beriberi,
is the result of a diet that is carbohydrate rich
and thiamin deficient. An additional thiamin deficiency
related disease is known as Wernicke-Korsakoff
syndrome. This disease is most commonly found
in chronic alcoholics due to their poor dietetic lifestyles.
Riboflavin
Riboflavin is also known as vitamin B2.
Riboflavin is the precursor for the coenzymes, flavin
mononucleotide (FMN) and flavin adenine dinucleotide
(FAD). The enzymes that require FMN or FAD as
cofactors are termed flavoproteins. Several flavoproteins
also contain metal ions and are termed metalloflavoproteins.
Both classes of enzymes are involved in a wide range
of redox reactions, e.g. succinate dehydrogenase and
xanthine oxidase. During the course of the enzymatic
reactions involving the flavoproteins the reduced
forms of FMN and FAD are formed, FMNH 2
and FADH 2, respectively.
The normal daily requirement for riboflavin
is 1.2 - 1.7 mg/day for normal adults.
Riboflavin deficiencies are rare in
the United States due to the presence of adequate
amounts of the vitamin in eggs, milk, meat and cereals.
Riboflavin deficiency is often seen in chronic alcoholics
due to their poor dietetic habits. Symptoms associated
with riboflavin deficiency include, glossitis, seborrhea,
angular stomatitis, cheilosis and photophobia. Riboflavin
decomposes when exposed to visible light. This characteristic
can lead to riboflavin deficiencies in newborns treated
for hyperbilirubinemia by phototherapy.
Niacin
Niacin (nicotinic acid and nicotinamide) is also known
as vitamin B3. Both nicotinic acid
and nicotinamide can serve as the dietary source of
vitamin B 3. Niacin is required for the
synthesis of the active forms of vitamin B 3,
nicotinamide adenine dinucleotide (NAD+)
and nicotinamide adenine dinucleotide phosphate
(NADP+). Both NAD + and NADP +
function as cofactors for numerous dehydrogenase,
e.g., lactate and malate dehydrogenases.
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Niacin is not a true vitamin in the
strictest definition since it can be derived from
the amino acid tryptophan. However, the ability to
utilize tryptophan for niacin synthesis is inefficient
(60 mg of tryptophan are required to synthesize 1
mg of niacin). Also, synthesis of niacin from tryptophan
requires vitamins B1, B2 and
B6 which would be limiting in themselves
on a marginal diet. The recommended daily requirement
for niacin is 13 - 19 niacin equivalents (NE) per
day for a normal adult. One NE is equivalent to 1
mg of free niacin).
A diet deficient in niacin (as well
as tryptophan) leads to glossitis of the tongue, dermatitis,
weight loss, diarrhea, depression and dementia. The
severe symptoms, depression, dermatitis and diarrhea,
are associated with the condition known as pellagra.
Several physiological conditions (e.g. Hartnup
disease and malignant carcinoid syndrome)
as well as certain drug therapies (e.g. isoniazid)
can lead to niacin deficiency. In Hartnup disease
tryptophan absorption is impaired and in malignant
carcinoid syndrome tryptophan metabolism is altered
resulting in excess serotonin synthesis. Isoniazid
(the hydrazide derivative of isonicotinic acid) is
the primary drug for chemotherapy of tuberculosis.
Nicotinic acid (but not nicotinamide) when administered
in pharmacological doses of 2 - 4 g/day lowers plasma
cholesterol levels and has been shown to be a useful
therapeutic for hypercholesterolemia.
The major action of nicotinic acid in this capacity
is a reduction in fatty acid mobilization from adipose
tissue. Although nicotinic acid therapy lowers blood
cholesterol it also causes a depletion of glycogen
stores and fat reserves in skeletal and cardiac muscle.
Additionally, there is an elevation in blood glucose
and uric acid production. For these reasons nicotinic
acid therapy is not recommended for diabetics or persons
who suffer from gout.
Pantothenic
Acid
Pantothenic acid is also known as vitamin B5.
Pantothenic acid is formed from b-alanine and pantoic
acid. Pantothenate is required for synthesis of coenzyme
A, CoA and is a component of the acyl carrier protein
(ACP) domain of fatty acid synthase. Pantothenate
is, therefore, required for the metabolism of carbohydrate
via the TCA cycle and all fats and proteins. At least
70 enzymes have been identified as requiring CoA or
ACP derivatives for their function. Deficiency of
pantothenic acid is extremely rare due to its widespread
distribution in whole grain cereals, legumes and meat.
Symptoms of pantothenate deficiency are difficult
to assess since they are subtle and resemble those
of other B vitamin deficiencies.
Vitamin
B6
Pyridoxal, pyridoxamine and pyridoxine
are collectively known as vitamin B6.
All three compounds are efficiently converted to the
biologically active form of vitamin B 6,
pyridoxal phosphate. This conversion is catalyzed
by the ATP requiring enzyme, pyridoxal kinase.
Pyridoxal phosphate functions as a cofactor in enzymes
involved in transamination reactions required for
the synthesis and catabolism of the amino acids as
well as in glycogenolysis as a cofactor for glycogen
phosphorylase. The requirement for vitamin B6
in the diet is proportional to the level of protein
consumption ranging from 1.4 - 2.0 mg/day for a normal
adult. During pregnancy and lactation the requirement
for vitamin B6 increases approximately
0.6 mg/day. Deficiencies of vitamin B6
are rare and usually are related to an overall deficiency
of all the B-complex vitamins. Isoniazid (see niacin
deficiencies above) and penicillamine (used to treat
rheumatoid arthritis and cystinurias) are two drugs
that complex with pyridoxal and pyridoxal phosphate
resulting in a deficiency in this vitamin.
Biotin is the cofactor required of
enzymes that are involved in carboxylation reactions,
e.g. acetyl-CoA carboxylase and pyruvate carboxylase.
Biotin is found in numerous foods and also is synthesized
by intestinal bacteria and as such deficiencies of the
vitamin are rare. Deficiencies are generally seen only
after long antibiotic therapies which deplete the intestinal
fauna or following excessive consumption of raw eggs.
The latter is due to the affinity of the egg white protein,
avidin, for biotin preventing intestinal absorption
of the biotin.
Cobalamin is more commonly known as
vitamin B12. Vitamin B12
is composed of a complex tetrapyrrol ring structure
(corrin ring) and a cobalt ion in the center. Vitamin
B12 is synthesized exclusively by microorganisms
and is found in the liver of animals bound to protein
as methycobalamin or 5'-deoxyadenosylcobalamin. The
vitamin must be hydrolyzed from protein in order to
be active. Hydrolysis occurs in the stomach by gastric
acids or the intestines by trypsin digestion following
consumption of animal meat. The vitamin is then bound
by intrinsic factor, a protein secreted by
parietal cells of the stomach, and carried to the
ileum where it is absorbed. Following absorption the
vitamin is transported to the liver in the blood bound
to transcobalamin II. There are only two clinically
significant reactions in the body that require vitamin
B12 as a cofactor. During the catabolism
of fatty acids with an odd number of carbon atoms
and the amino acids valine, isoleucine and threonine
the resultant propionyl-CoA is converted to succinyl-CoA
for oxidation in the TCA cycle. One of the enzymes
in this pathway, methylmalonyl-CoA mutase, requires
vitamin B12 as a cofactor in the conversion
of methylmalonyl-CoA to succinyl-CoA. The 5'-deoxyadenosine
derivative of cobalamin is required for this reaction.
The second reaction requiring vitamin B12
catalyzes the conversion of homocysteine to methionine
and is catalyzed by methionine synthase. This reaction
results in the transfer of the methyl group from N5-methyltetrahydrofolate
to hydroxycobalamin generating tetrahydrofolate (THF)
and methylcobalamin during the process of the conversion.
The liver can store up to six years
worth of vitamin B12, hence deficiencies
in this vitamin are rare. Pernicious
anemia is a megaloblastic anemia resulting from
vitamin B12 deficiency that develops as
a result a lack of intrinsic factor in the stomach
leading to malabsorption of the vitamin. The anemia
results from impaired DNA synthesis due to a block
in purine
and thymidine biosynthesis. The block in nucleotide
biosynthesis is a consequence of the effect of vitamin
B12 on folate metabolism. When vitamin
B12 is deficient essentially all of the
folate becomes trapped as the N5-methylTHF
derivative as a result of the loss of functional methionine
synthase. This trapping prevents the synthesis of
other THF derivatives required for the purine and
thymidine nucleotide biosynthesis pathways. Neurological
complications also are associated with vitamin B12
deficiency and result from a progressive demyelination
of nerve cells. The demyelination is thought to result
from the increase in methylmalonyl-CoA that result
from vitamin B12 deficiency. Methylmalonyl-CoA
is a competitive inhibitor of malonyl-CoA in fatty
acid biosynthesis as well as being able to substitute
for malonyl-CoA in any fatty acid biosynthesis that
may occur. Since the myelin sheath is in continual
flux the methylmalonyl-CoA-induced inhibition of fatty
acid synthesis results in the eventual destruction
of the sheath. The incorporation methylmalonyl-CoA
into fatty acid biosynthesis results in branched-chain
fatty acids being produced that may severely alter
the architecture of the normal membrane structure
of nerve cells
Folic acid is a conjugated molecule consisting of
a pteridine ring structure linked to para-aminobenzoic
acid (PABA) that forms pteroic acid. Folic
acid itself is then generated through the conjugation
of glutamic acid residues to pteroic acid. Folic acid
is obtained primarily from yeasts and leafy vegetables
as well as animal liver. Animal cannot synthesize
PABA nor attach glutamate residues to pteroic acid,
thus, requiring folate intake in the diet. When stored
in the liver or ingested folic acid exists in a polyglutamate
form. Intestinal mucosal cells remove some of the
glutamate residues through the action of the lysosomal
enzyme, conjugase. The removal of glutamate residues
makes folate less negatively charged (from the polyglutamic
acids) and therefore more capable of passing through
the basal lamenal membrane of the epithelial cells
of the intestine and into the bloodstream. Folic acid
is reduced within cells (principally the liver where
it is stored) to tetrahydrofolate (THF also H4folate)
through the action of dihydrofolate reductase (DHFR),
an NADPH-requiring enzyme. The function of THF derivatives
is to carry and transfer various forms of one carbon
units during biosynthetic reactions. The one carbon
units are either methyl, methylene, methenyl, formyl
or formimino groups.
These one carbon transfer reactions
are required in the biosynthesis of serine, methionine,
glycine, choline and the purine nucleotides and dTMP.
The ability to acquire choline and amino acids from
the diet and to salvage the purine nucleotides makes
the role of N5,N10-methylene-THF
in dTMP synthesis the most metabolically significant
function for this vitamin. The role of vitamin B12
and N5-methyl-THF in the conversion of
homocysteine to methionine also can have a significant
impact on the ability of cells to regenerate needed
THF.
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Folate deficiency results in complications
nearly identical to those described for vitamin B12
deficiency. The most pronounced effect of folate deficiency
on cellular processes is upon DNA synthesis. This
is due to an impairment in dTMP synthesis which leads
to cell cycle arrest in S-phase of rapidly proliferating
cells, in particular hematopoietic cells. The result
is megaloblastic anemia as for vitamin B12
deficiency. The inability to synthesize DNA during
erythrocyte maturation leads to abnormally large erythrocytes
termed macrocytic anemia. Folate deficiencies
are rare due to the adequate presence of folate in
food. Poor dietary habits as those of chronic alcoholics
can lead to folate deficiency. The predominant causes
of folate deficiency in non-alcoholics are impaired
absorption or metabolism or an increased demand for
the vitamin. The predominant condition requiring an
increase in the daily intake of folate is pregnancy.
This is due to an increased number of rapidly proliferating
cells present in the blood. The need for folate will
nearly double by the third trimester of pregnancy.
Certain drugs such as anticonvulsants and oral contraceptives
can impair the absorption of folate. Anticonvulsants
also increase the rate of folate metabolism.
Ascorbic acid is more commonly known
as vitamin C. Ascorbic acid is derived from glucose
via the uronic acid pathway. The enzyme L-gulonolactone
oxidase responsible for the conversion of gulonolactone
to ascorbic acid is absent in primates making ascorbic
acid required in the diet. The active form of vitamin
C is ascorbate acid itself. The main function of ascorbate
is as a reducing agent in a number of different reactions.
Vitamin C has the potential to reduce cytochromes a
and c of the respiratory chain as well as molecular
oxygen. The most important reaction requiring ascorbate
as a cofactor is the hydroxylation of proline residues
in collagen. Vitamin C is, therefore, required for the
maintenance of normal connective tissue as well as for
wound healing since synthesis of connective tissue is
the first event in wound tissue remodeling. Vitamin
C also is necessary for bone remodeling due to the presence
of collagen in the organic matrix of bones. Several
other metabolic reactions require vitamin C as a cofactor.
These include the catabolism of tyrosine and the synthesis
of epinephrine from tyrosine and the synthesis of the
bile acids. It is also believed that vitamin C is involved
in the process of steroidogenesis since the adrenal
cortex contains high levels of vitamin C which are depleted
upon adrenocorticotropic hormone (ACTH) stimulation
of the gland. Deficiency in vitamin C leads to the disease
scurvy due to the role of the vitamin in the
post-translational modification of collagens. Scurvy
is characterized by easily bruised skin, muscle fatigue,
soft swollen gums, decreased wound healing and hemorrhaging,
osteoporosis, and anemia. Vitamin C is readily absorbed
and so the primary cause of vitamin C deficiency is
poor diet and/or an increased requirement. The primary
physiological state leading to an increased requirement
for vitamin C is severe stress (or trauma). This is
due to a rapid depletion in the adrenal stores of the
vitamin. The reason for the decrease in adrenal vitamin
C levels is unclear but may be due either to redistribution
of the vitamin to areas that need it or an overall increased
utilization.
Vitamin A consists of three biologically
active molecules, retinol, retinal (retinaldehyde)
and retinoic acid.
Each of these compounds are derived
from the plant precursor molecule, b-carotene
(a member of a family of molecules known as carotenoids).
Beta-carotene, which consists of two molecules of retinal
linked at their aldehyde ends, is also referred to as
the provitamin form of vitamin A. Ingested b-carotene
is cleaved in the lumen of the intestine by b-carotene
dioxygenase to yield retinal. Retinal is reduced to
retinol by retinaldehyde reductase, an NADPH requiring
enzyme within the intestines. Retinol is esterified
to palmitic acid and delivered to the blood via chylomicrons.
The uptake of chylomicron remnants by the liver results
in delivery of retinol to this organ for storage as
a lipid ester within lipocytes. Transport of retinol
from the liver to extrahepatic tissues occurs by binding
of hydrolyzed retinol to aporetinol binding protein
(RBP). the retinol-RBP complex is then transported
to the cell surface within the Golgi and secreted. Within
extrahepatic tissues retinol is bound to cellular
retinol binding protein (CRBP). Plasma transport
of retinoic acid is accomplished by binding to albumin.
Within cells both retinol and retinoic
acid bind to specific receptor proteins. Following
binding, the receptor-vitamin complex interacts with
specific sequences in several genes involved in growth
and differentiation and affects expression of these
genes. In this capacity retinol and retinoic acid
are considered hormones of the steroid/thyroid hormone
superfamily of proteins. Vitamin D also acts in a
similar capacity. Several genes whose patterns of
expression are altered by retinoic acid are involved
in the earliest processes of embryogenesis including
the differentiation of the three germ layers, organogenesis
and limb development.
Photoreception in the eye is the function
of two specialized cell types located in the retina;
the rod and cone cells. Both rod and cone cells contain
a photoreceptor pigment in their membranes. The photosensitive
compound of most mammalian eyes is a protein called
opsin to which is covalently coupled an aldehyde
of vitamin A. The opsin of rod cells is called scotopsin.
The photoreceptor of rod cells is specifically called
rhodopsin or visual purple. This compound
is a complex between scotopsin and the 11-cis-retinal
(also called 11-cis-retinene) form of vitamin
A. Rhodopsin is a serpentine receptor imbedded in
the membrane of the rod cell. Coupling of 11-cis-retinal
occurs at three of the transmembrane domains of rhodopsin.
Intracellularly, rhodopsin is coupled to a specific
G-protein called transducin. When the rhodopsin
is exposed to light it is bleached releasing
the 11-cis-retinal from opsin. Absorption of
photons by 11-cis-retinal triggers a series
of conformational changes on the way to conversion
all-trans-retinal. One important conformational
intermediate is metarhodopsin II. The release
of opsin results in a conformational change in the
photoreceptor. This conformational change activates
transducin, leading to an increased GTP-binding by
the a-subunit of transducin. Binding of GTP releases
the a-subunit from the inhibitory b- and g-subunits.
The GTP-activated a-subunit in turn activates an associated
phosphodiesterase; an enzyme that hydrolyzes cyclic-GMP
(cGMP) to GMP. Cyclic GMP is required to maintain
the Na+ channels of the rod cell in the
open conformation. The drop in cGMP concentration
results in complete closure of the Na+
channels. Metarhodopsin II appears to be responsible
for initiating the closure of the channels. The closing
of the channels leads to hyperpolarization of the
rod cell with concomitant propagation of nerve impulses
to the brain.
Retinol also functions in the synthesis
of certain glycoproteins and mucopolysaccharides necessary
for mucous production and normal growth regulation.
This is accomplished by phosphorylation of retinol
to retinyl phosphate which then functions similarly
to dolichol phosphate.
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Vitamin A is stored in the liver and
deficiency of the vitamin occurs only after prolonged
lack of dietary intake. The earliest symptoms of vitamin
A deficiency are night blindness. Additional
early symptoms include follicular hyperkeratinosis,
increased susceptibility to infection and cancer and
anemia equivalent to iron deficient anemia. Prolonged
lack of vitamin A leads to deterioration of the eye
tissue through progressive keratinization of the cornea,
a condition known as xerophthalmia. The increased
risk of cancer in vitamin deficiency is thought to
be the result of a depletion in b-carotene. Beta-carotene
is a very effective antioxidant and is suspected to
reduce the risk of cancers known to be initiated by
the production of free radicals. Of particular interest
is the potential benefit of increased b-carotene intake
to reduce the risk of lung cancer in smokers. However,
caution needs to be taken when increasing the intake
of any of the lipid soluble vitamins. Excess accumulation
of vitamin A in the liver can lead to toxicity which
manifests as bone pain, hepatosplenomegaly, nausea
and diarrhea.
Vitamin D is a steroid hormone that
functions to regulate specific gene expression following
interaction with its intracellular receptor. The biologically
active form of the hormone is 1,25-dihydroxy vitamin
D3 (1,25-(OH)2D3,
also termed calcitriol). Calcitriol functions
primarily to regulate calcium and phosphorous homeostasis.
Active calcitriol is derived from ergosterol
(produced in plants) and from 7-dehydrocholesterol
(produced in the skin). Ergocalciferol (vitamin
D2) is formed by uv irradiation of ergosterol.
In the skin 7-dehydrocholesterol is converted to cholecalciferol
(vitamin D3) following uv irradiation.
Vitamin D2 and D3 are processed
to D2-calcitriol and D3-calcitriol,
respectively, by the same enzymatic pathways in the
body. Cholecalciferol (or egrocalciferol) are absorbed
from the intestine and transported to the liver bound
to a specific vitamin D-binding protein. In the
liver cholecalciferol is hydroxylated at the 25 position
by a specific D3-25-hydroxylase generating
25-hydroxy-D3 [25-(OH)D3] which
is the major circulating form of vitamin D. Conversion
of 25-(OH)D3 to its biologically active form,
calcitriol, occurs through the activity of a specific
D3-1-hydroxylase present in the proximal
convoluted tubules of the kidneys, and in bone and placenta.
25-(OH)D3 can also be hydroxylated at the
24 position by a specific D3-24-hydroxylase
in the kidneys, intestine, placenta and cartilage.
Calcitriol functions in concert with parathyroid
hormone (PTH) and calcitonin to regulate
serum calcium and phosphorous levels. PTH is released
in response to low serum calcium and induces the production
of calcitriol. In contrast, reduced levels of PTH stimulate
synthesis of the inactive 24,25-(OH)2D3.
In the intestinal epithelium, calcitriol functions as
a steroid hormone in inducing the expression of calbindinD28K,
a protein involved in intestinal calcium absorption.
The increased absorption of calcium ions requires concomitant
absorption of a negatively charged counter ion to maintain
electrical neutrality. The predominant counter ion is
Pi. When plasma calcium levels fall the major sites
of action of calcitriol and PTH are bone where they
stimulate bone resorption and the kidneys where they
inhibit calcium excretion by stimulating reabsorption
by the distal tubules. The role of calcitonin in calcium
homeostasis is to decrease elevated serum calcium levels
by inhibiting bone resorption.
As a result of the addition of vitamin
D to milk, deficiencies in this vitamin are rare in
this country. The main symptom of vitamin D deficiency
in children is rickets and in adults is osteomalacia.
Rickets is characterized improper mineralization during
the development of the bones resulting in soft bones.
Osteomalacia is characterized by demineralization
of previously formed bone leading to increased softness
and susceptibility to fracture.
Vitamin
E
Vitamin E is a mixture of several related compounds
known as tocopherols. The a-tocopherol molecule
is the most potent of the tocopherols. Vitamin E is
absorbed from the intestines packaged in chylomicrons.
It is delivered to the tissues via chylomicron transport
and then to the liver through chylomicron remnant
uptake. The liver can export vitamin E in VLDLs. Due
to its lipophilic nature, vitamin E accumulates in
cellular membranes, fat deposits and other circulating
lipoproteins. The major site of vitamin E storage
is in adipose tissue. The major function of vitamin
E is to act as a natural antioxidant by scavenging
free radicals and molecular oxygen. In particular
vitamin E is important for preventing peroxidation
of polyunsaturated membrane fatty acids. The vitamins
E and C are interrelated in their antioxidant capabilities.
Active a-tocopherol can be regenerated by interaction
with vitamin C following scavenge of a peroxy free
radical. Alternatively, a-tocopherol can scavenge
two peroxy free radicals and then be conjugated to
glucuronate for excretion in the bile.
No major disease states have been found
to be associated with vitamin E deficiency due to
adequate levels in the average American diet. The
major symptom of vitamin E deficiency in humans is
an increase in red blood cell fragility. Since vitamin
E is absorbed from the intestines in chylomicrons,
any fat malabsorption diseases can lead to deficiencies
in vitamin E intake. Neurological disorders have been
associated with vitamin E deficiencies associated
with fat malabsorptive disorders. Increased intake
of vitamin E is recommended in premature infants fed
formulas that are low in the vitamin as well as in
persons consuming a diet high in polyunsaturated fatty
acids. Polyunsaturated fatty acids tend to form free
radicals upon exposure to oxygen and this may lead
to an increased risk of certain cancers.
The K vitamins exist naturally as K1
(phylloquinone) in green vegetables and K2
(menaquinone) produced by intestinal bacteria and
K3 is synthetic menadione. When administered,
vitamin K3 is alkylated to one of the vitamin
K2 forms of menaquinone.
The major function of the K vitamins
is in the maintenance of normal levels of the blood
clotting proteins, factors II, VII, IX, X
and protein C and protein S, which are
synthesized in the liver as inactive precursor proteins.
Conversion from inactive to active clotting factor requires
a posttranslational
modification of specific glutamate (E) residues.
This modification is a carboxylation and the enzyme
responsible requires vitamin K as a cofactor. The resultant
modified E residues are g-carboxyglutamate (gla).
This process is most clearly understood for factor II,
also called preprothrombin. Prothrombin is modified
preprothrombin. The gla residues are effective
calcium ion chelators. Upon chelation of calcium, prothrombin
interacts with phospholipids in membranes and is proteolysed
to thrombin through the action of activated factor X
(Xa). During the carboxylation reaction reduced hydroquinone
form of vitamin K is converted to a 2,3-epoxide form.
The regeneration of the hydroquinone form requires an
uncharacterized reductase. This latter reaction is the
site of action of the dicumarol based anticoagulants
such as warfarin.
Naturally occurring vitamin K is absorbed
from the intestines only in the presence of bile salts
and other lipids through interaction with chylomicrons.
Therefore, fat malabsorptive diseases can result in
vitamin K deficiency. The synthetic vitamin K3
is water soluble and absorbed irrespective of the
presence of intestinal lipids and bile. Since the
vitamin K2 form is synthesized by intestinal
bacteria, deficiency of the vitamin in adults is rare.
However, long term antibiotic treatment can lead to
deficiency in adults. The intestine of newborn infants
is sterile, therefore, vitamin K deficiency in infants
is possible if lacking from the early diet. The primary
symptom of a deficiency in infants is a hemorrhagic
syndrome.
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