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Vitamins

Authors:
Drs Peter Nixon, Susan
Hamilton and Craig Zimitat,
Department of Biochemistry.
nixonp@biosci.uq.edu.au
hamilton@biosci.uq.edu.au

Keywords
vitamins
thiamin
coenzyme
B vitamins

General Introduction to vitamins

The following texts provide good overviews of the biochemistry of
the vitamins:
Wills' Biochemical Basis of Medicine (3rd edition, 1997) by Brian
Gillham, Despo Papachristodoulou and J. Hywel Thomas.
Butterworth-Heinmann QP514.2 W54 1997
Nutritional Biochemistry (2nd edition, 1999) by Thomas Brody.
Academic Press QP141.B853 1999
Nutritional Biochemistry and Metabolism with Clinical
Applications (1991) by Maria C. Linder.
Appleton & Lange QP141.N86
Principles of Biochemistry; Mammalian Biochemistry, 7th Edtn
(1983) by E.L. Smith, Hill, Lehman, Lefkowitz, Handler and
White. McGraw Hill QP514.W45
Harrison's Textbook of Medicine, including Harrison's OnLine
The following monograph provides authoritative, current reviews
of individual topics in nutrition, including vitamins and is for those
seeking greater depth in particular topics.
Present Knowledge in Nutrition, 7th Edtn (1996), Eds Ekhard E.
Ziegler & L.J. Filer, Jr. TX551.P7 in HML & Gatton libraries.

B VITAMINS - THEIR ROLE AND

CONSEQUENCES OF DEFICIENCIES.

THE

Despite the considerable present knowledge of vitamins and their

functions, vitamin deficiency diseases do still occur. Vulnerable
groups in our society include those who are shut-ins such as the
elderley, those who consume a fad diet (without vitamins) such as
some weight-reduction programs, and especially alcoholics.
Particular diseases causing anorexia, such as cancer of the stomach,
also cause malnutrition including vitamin malnutrition. One disease
due to deficiency of vitamin B1 (thiamin) damages particular parts
of the brain and can be recognised at post mortem examination of
the brain: it is found in more than 2% of the brains examined in
hospitals in Australia and in 1.8% of those examined in USA and
Norway. (There are now 3 teaching hospitals in USA, 1 in Norway
and 2 in Australia where comprehensive postmortem examinations
of all brains have been carried out.)

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Vitamins are compounds that are absolutely required for health, in
only small amounts, and that must be supplied preformed in the
diet. There is always some organism that makes each vitamin de
novo; in the case of vitamins required by humans, frequently the
ultimate source of biosynthesis is bacteria, although sometimes the
source can be plants or even non-primate animals. Thus each
species has its own list of essential compounds that it cannot make;
i.e. the concept of vitamin implies species specificity, although there
is considerable overlap between species.
This week you should become familiar with the functions of
selected vitamins: B1 or thiamin, B2 or riboflavin, B3 or niacin,
B5 or pantothenic acid, B6 or pyridoxine and H or Biotin. Like
most vitamins, they are precursors of compounds that have cofactor
activity when bound with particular proteins (apoenzymes). The
resultant holoenzyme is active whereas the apoenzyme alone is
inactive. The vitamins are often very special chemicals, such as
heterocycles, and the holoenzymes are able to catalyse remarkable
chemical reactions that are impossible without these biological
catalysts. The vitamins B 1, 2, 3, 5 and 6 and biotin each plays a
role as cofactor in several essential reactions of energy metabolism
or amino acid metabolism.

EXERCISE - RECOGNISE THE UBIQUITOUS ROLE

OF VITAMINS IN METABOLISM
Take your comprehensive textbook of biochemistry, e.g. Garrett &
Grisham, Lehninger, Mathew & van Holde or Voet & Voet or
whatever, and in the index look up the reactions catalysed by
enzymes containing the cofactors derived from the above vitamins.
These are: thiamin diphosphate
(ThDP) from B1, flavin
mononucleotide (FMN) or flavin dinucleotide (FAD) from B2,
nicotinamide adenine dinucleotide (NAD & NADH) and also
nicotinamide adenine phosphate dinucleotide (NADP & NADPH)
from B3, Coenzyme A from B5, pyridoxal phosphate from B6,
and unaltered biotin. In energy metabolism alone, these play an
essential role as cofactors (also known as coenzymes) in a large
proportion of important enzyme-catalysed reactions. Recognise
that there are also coenzymes that humans can make, and which are
therefore NOT derived from vitamins. Perhaps the best-known of
these is the haem group, found in haemoglobin and in cytochromes,
although even in this case the iron component is an essential mineral
nutrient.
VITAMIN-DEFICIENCY DISEASES
Isolated deficiencies of individual vitamins do occur spontaneously
in man, particularly of B1, folic acid, B12 and C. Isolated
deficiencies of other vitamins are observed only in exceptional
circumstances but these are not uncommon in modern medicine:
for example, in prolonged artificial feeding for diseases of the

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jejunum and ileum, accompanied by failure to recognise the
complete human need. Combined deficiency of several vitamins
together (e.g. B2, B3 and B6) is a feature of generalised
malnutrition that is often accompanied by protein malnutrition.
The characteristics of diseases due to deficiency of vitamins B1B6 need to be recognised, namely pellagra, beriberi (a metabolic
cause of peripheral neuritis or peripheral neuropathy) and the
Wernicke-Korsakoff syndrome (sometimes known as central
nervous system beriberi). Pellagra reflects deficiency of B3, usually
combined with deficiencies of other B vitamins and of proteins and
is characterised by dermatitis of areas exposed to sunlight;
stomatitis, an atrophic, sore, magenta-coloured tongue; impaired
digestion; diarrhea; hemorrhages from the GIT in severe cases;
CNS disturbances leading to dementia; and death when the disease
goes untreated. In 19th and early 20th centuries, mental hospitals
were devoted to caring for pellagrins and death due to pellagra was
endemic in north America and in southern Europe. Deficiency of
B1 is introduced below. For isolated deficiencies and more details
of pellagra refer to texts below.
Functions of other vitamins and the consequences of insufficient
nutriture of those vitamins will be met elsewhere: folic acid (B10),
cobalamins (B12), C, A, D, E and K. There are some other B
vitamins whose functions are important but which are seldom so
deficient as to give rise to important diseases in man. These include
biotin, choline, inositol, lipoic acid and perhaps para-amino benzoic
acid.
The texts above provide accounts of vitamin function and vitamin
deficiency diseases with differing emphases and scope. Linder is
comprehensive but inaccurate; Brody is accurate, comprehensive
but lengthy; Wills is perhaps too brief. Older editions of Harrison's
textbook of medicine were able to devote more space to the vitamin
deficiency diseases than the current edition.
A special case - linking biochemical malfunction to brain
damage in thiamin deficiency
Just which thiamin-dependent enzymes of the brain and which
aspects of brain metabolism are most affected by thiamin deficiency
are questions that address aspects of the pathogenesis of brain
damage due to thiamin deficiency. Some reviews of research in this
area are listed below.
Butterworth, R.F. 1989 Effects of thiamine deficiency on brain
metabolism: implications for the pathogenesis of the WernickeKorsakoff syndrome. Alcohol & Alcoholism 24, 271-279.
Heroux, M. and Butterworth, R.F. 1995 Regional alterations of
thiamine phosphate esters and of thiamine diphosphate-dependent

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enzymes in relation to function in experimental Wernickes
encephalopathy. Neurochemical Research 20, 87-93.
Thiamin deficiency: mechanisms of brain damage.
Our knowledge of thiamin deficiency comes from studies of:
feeding rats synthetic diets deficient in thiamin ;
poorly nourished people and alcoholics;
in vitro, and more recently, in vivo biochemical research on
metabolic processes; and
molecular biology approaches to study of thiamin-dependent
enzymes.
Acute thiamin deficiency results in clinical signs of disease (ataxia,
eye signs, confabulation) before the onset of brain damage.
Neuropathology typically involves bilaterally symmetrical lesions in
the mamillary bodies and the nuclei of the midbrain in the floor of
the IVth ventricle. If thiamin is required by all cells, why are only
specific areas of the brain damaged in acute thiamin deficiency ?
This is an area of active research and the comments below are
largely provided as a stimulus for thought. Remember there is not
yet a final solution to the question what causes the specific lesions
seen in thiamin deficiency?.
Early researchers believed that the areas of the brain affected by
thiamin deficiency were selectively vulnerable to thiamin
depletion. It has been shown that there is a decrease in total
thiamin and a decrease of thiamin diphosphate in the affected
brain regions when compared with unaffected brain regions.
Since the biological role of thiamin is catalytic, research turned
towards the thiamin dependent enzymes.
The enzymes involved include transketolase (TK), pyruvate
dehydrogenase (PDH) and oxo-glutarate dehydrogenase
(OGDH)(also called alpha-keto glutarate dehydrogenase). The
activity of these enzymes was measured in brain tissue extracts
from thiamin deficient rats. The maximal activity of cerebral
PDH was not significantly affected during thiamin deficiency in
rats, or after reversal by thiamin administration. (The in vivo
activity of PDH however may be diminished either due to loss of
cofactor or regulation.) The activity of TK decreased in affected
areas of thiamin deficient rat brains before the onset of clinical
signs of disease, but remained depressed after the reversal of
deficiency by the administration of thiamin. Lastly, the activity of
OGDH decreased as signs of thiamin deficiency became more
severe and returned towards normal after administration of
thiamin. Thus, only the activity of OGDH correlated well with
the progression of thiamin deficiency disease.
The administration of a glucose load to thiamin deficient rats can

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precipitate episodes of gross neurological dysfunction leading to
death. NMR spectroscopy has revealed an increase in total
glutamate concentration in the brains of thiamin deficient rats
after a glucose load and this is consistent with a decrease in the
activity of OGDH. (Check the pathways.) In advanced thiamin
deficiency, lactate accumulates rapidly following a glucose load
and this is consistent with a metabolic block at the level of
OGDH and/or PDH. Where the glutamate is accumulating is
unclear ... is it intracellular or extracellular ? is it due to
abnormal neuronal or astrocytic metabolism, or both?
The focal accumulation of extracellular glutamate in areas of the
brain affected by thiamin deficiency has led some investigators to
conclude that glutamate excitotoxicity is the main cause of cell
death in thiamin deficient brain. This has achieved further
recognition since the demonstration that administration of
MK801 (an NMDA glutamate receptor antagonist) to thiamindeficient rats before the onset of clinical signs of thiamin
deficiency (eg ataxia) can totally prevent the appearance of
lesions. At present there is no evidence of specific upregulation
(or downregulation) of glutamate receptors in the thiamindeficient rat brain. The question remains where does this
glutamate come from ? Is it a case of excess production or a
case of failure of uptake mechanisms ...
The earliest histological changes seen in the thiamin-deficient rat
brain involve oedema of glial foot processes along the blood
brain barrier. Some changes in blood brain barrier permeability
have been observed in alcohol treated rats and these are more
severe in alcohol-treated thiamin-deficient rats than alcohol-free
controls. The exact role of the blood brain barrier in the
neuropathology of thiamin deficiency is unresolved, but the BBB
does have NMDA-glutamate receptors which may affect
function.
How much brain damage is due to ethanol and how much to
thiamin deficiency ?
Thiamin deficiency is seen primarily in the alcoholic population, but
how much of the pathology is due to alcohol and how much is due
to thiamin deficiency? Supplementation of alcoholic beverages in
Canada lead to a significant reduction in the incidence of WE. The
coincident consumption of alcohol and thiamin deficiency does lead
to more extensive lesions than either alcohol consumtion or thiamin
deficiency alone. One recent study has shown that mega-doses of
thiamin (1g/kg food) can totally prevent the brain damage due to
ethanol consumption in rats, whereas high doses (0.1 mg/kg food)
do not.