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Metabolic and Structural Role of Thiamine in Nervous Tissues

Article  in  Cellular and Molecular Neurobiology · November 2008

DOI: 10.1007/s10571-008-9297-7 · Source: PubMed

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Abdoulaye Bâ
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Cell Mol Neurobiol (2008) 28:923–931
DOI 10.1007/s10571-008-9297-7

REVIEW

Metabolic and Structural Role of Thiamine in Nervous

Tissues
Abdoulaye Bâ

Received: 9 March 2007 / Accepted: 30 June 2008 / Published online: 19 July 2008
Ó Springer Science+Business Media, LLC 2008

Abstract In the literature, previous descriptions of Keywords Thiamine deficiency

the role of thiamine (B1 vitamin) focused mostly on Developing brain
Metabolic and structural role
its biochemical functions as a coenzyme precursor of
some key enzymes of the carbohydrate metabolism.
This report reviews recent developments on the
metabolic and structural role of thiamine, e.g., the Introduction
coenzyme and noncoenzyme functions of the vita-
min. Taking into account analysis of our The brain uses glucose as a primary fuel for energy
experimental data relating to the effects of thiamine generation. Glucose gains entry into the brain by
deficiency on developing central nervous system facilitated diffusion across the blood–brain barrier
(CNS) and data available in literature, we seek to (Rao and Seaquist 2006). Roughly, 30% of the
establish a clear difference between the metabolic glucose absorbed by the brain undergoes a complete
and structural role of thiamine. Our experimental data oxidation through the tricarboxylic acid cycle (Sie-
indicate that the specific and nonspecific effects bert et al. 1986). Three enzymatic systems, essential
express two diametrically diverse functions of thia- for the cerebral metabolism of glucose, depend on
mine in development: the nonspecific effects show up thiamine (B1 vitamin): The mitochondrial pyruvate
the metabolic consequences of thiamine deficiency and a-ketoglutarate dehydrogenases complexes and
resulting in apoptosis and severe cellular deficit; the cytosolic transketolase (Martin et al. 2003). These
inversely, the specific effects announced the struc- three enzymes use, as cofactor, the thiamine pyro-
tural consequences of thiamine deficiency, described phosphate (TPP) which accounts for 80% of total
as cellular membrane damage, irregular and ectopic thiamine present in nervous tissues (Ishii et al. 1979).
cells. The review highlights the existence of non- In the literature, the major part of actions of the
coenzyme functions of this vitamin through its thiamine described in nervous tissues is limited to
interactions with biological membranes. those metabolic aspects which show up the co-
enzymatic function of the vitamin (Butterworth
1987). However, literature that takes an interest in
the structural role of thiamine is growing. So,
thiamine interferes with the membrane structure
A. Bâ (&) and function (Tanaka and Cooper 1968; Itokawa
Université de Cocody, UFR Biosciences, 22 BP 582,
Abidjan 22, Ivory Coast et al. 1972; Goldberg et al. 2004), acts against
e-mail: [email protected] agents-induced cytotoxicity (Bâ et al. 1996; Aberle

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924 Cell Mol Neurobiol (2008) 28:923–931

et al. 2004) and fixes membrane sites (Czerniecki reduced quantity of regular diet matched to the TD
et al. 2004; Spector and Johanson 2007). Those dams’ consumption. The malnutrition generated by
observations illustrate the noncoenzymatic function every pattern of thiamine deficiency was controlled
of the vitamin. We reported the metabolic to be by its own PF group. For each pattern of thiamine
different from the structural role of thiamine in deficiency, we made multiple comparisons between
nervous tissues, constantly (Bâ et al. 1996, 2005; Bâ C-TD-PF data recorded on the corresponding off-
2005). This review attempts through discussion to spring (Bâ 2005): Specific effect, e.g., effect caused
differentiate the metabolic from structural role of by thiamine lack per se was diagnosed if
thiamine, in other words, to separate the coenzyme C = TD = PF; nonspecific effect, e.g., effect of
and noncoenzyme functions of the vitamin. malnutrition that comes with a thiamine deprivation
Studies of the thiamine metabolism variations are was identified when C = TD = PF. On the 45th
often achieved according to chronic alcoholism. postnatal day, histologic studies were done on the
Chronic alcoholism weakens the metabolism of brains of the offspring and the structure of the
thiamine by a reduction of the rate of enzymes hippocampus was examined (Fig. 2a). Average reduc-
dependent on the vitamin (Butterworth 1989). In tion rate in nuclear size and density was assessed
addition, the Fetal Alcohol Syndrome (FAS) was following each pattern of thiamine deficiency, within
commonly described in children born to severely the dentate gyrus and the fields CA4, CA3 and CA1 of
alcoholic mothers (Jones and Smith 1973). The the hippocampus (Fig. 2a), (Bâ et al. 2005).
Intrauterine Growth Retardation (IUGR), a frequent
concomitant of FAS, was suggested to result from the
effects of ethanol-induced thiamine deficiency Developmental Thiamine Deficiency
(Rœcklin et al. 1985).
In our studies, we investigated in the rat, exper- Figure 1 summarizes profiles from four typical
imental models of FAS (Bâ et al. 1996, 1999) and effects of developmental thiamine deficiencies on
IUGR (Bâ 2005; Bâ et al. 2005). For further under- the CNS, gathered through our previous studies
standing of the role of the thiamine in nervous tissues, (Bâ 2005; Bâ et al. 1999, 2005), e.g., specific and
we have studied the effects of thiamine deficiency on nonspecific effects, cellular death and atrophy, which
the developing central nervous system (CNS), (Bâ were statistically assessed from prenatal to postnatal
2005; Bâ et al. 2005). Thus, thiamine deficiency was periods.
induced during three main periods of the rat CNS
ontogenesis. Females were fed with a thiamine Developmental Thiamine deficiency
70
deficient diet during the periods of gestation and
lactation; fetuses were exposed alternatively to pre-,
60
peri- or postnatal thiamine deficiency. Thereafter, the
effects of maternal thiamine deprivation were 50
assessed on the development of psychomotor and
Non-specific effects
Percentages

sensory functions in the offspring: seven different 40 Specific effects

developmental abilities (exploratory activity, emo- Cellular death
tional reaction, hind paws lifting reflex, wire grasping 30 Cellular atrophy

times, crawling and leap execution latencies, and

nociception) were recorded in the offspring from the 20

10th to the 45th postnatal day (Bâ and Seri 1993,

10
1995), to assess the specific and nonspecific effects of
maternal thiamine deficiency on fetal brain (Bâ
0
2005). Prenatal Perinatal Postnatal
Control dams (C) received regular diet containing Thiamine deficiency
thiamine during gestation and lactation. B1 lack-
Fig. 1 Profiles of four typical effects of developmental
induced anorexia in thiamine deficient dams (TD) was thiamine deficiency on the CNS. Extract from data published
reproduced in pair-fed dams (PF) which received a elsewhere (Bâ 2005; Bâ et al. 1999, 2005)

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Cell Mol Neurobiol (2008) 28:923–931 925

Our results show that the percentage of functions

altered by the specific lack of B1 vitamin increases
from prenatal (28.57%) to perinatal (42.85%) and to
postnatal periods (57.14%). Inversely, the percentage
of functions altered by the nonspecific effects of
thiamine deficiency decreases from prenatal
(60.14%) to perinatal (35.31%) and postnatal periods
(14.32%), (Fig. 1), (Bâ 2005).
It appears also that the rate of cellular death,
resulting from thiamine deficiency, decreases pro-
gressively from prenatal (39.97%) to perinatal
(26.75%) and postnatal periods (14.92%), whereas
cellular atrophy does not seem to show any percep-
tible variations from prenatal (7.97%) to peri-
(12.95%) and postnatal (10.77%) periods (Fig. 1),
(Bâ et al. 2005).
Statistical analysis shows that the specific and
nonspecific effects of thiamine deficiency, on the
functional development of the CNS, are negatively
correlated (R = -0.9988, t = 20.39, P \ 0.025).
Cellular death exhibits a positive correlation with
the nonspecific effects of thiamine deficiency
(R = 0.9998, t = 49.99, P \ 0.01) and negative with
the specific effects of that deficiency (R = -0.9994,
t = 28.85, P \ 0.025), during development. Cellular
atrophy does not show any significant correlation
with either the nonspecific effects (R = -0.5997,
t = 0.75, P [ 0.1) or the specific effects of thiamine
deficiency (R = 0.5606, t = 0.67, P [ 0.1).
For a better illustration of our goal, we compare in
Fig. 2c and d, the effects of pre- and postnatal
thiamine deficiencies on qualitative morphological
alterations assessed from the hilar CA3 pyramidal
cells of the hippocampus (Fig. 2a). Figure 2c shows
that prenatal thiamine deficiency was characterized
by a singular deficit of CA3 pyramidal cells com-
Fig. 2 (a) Parasagittal sections of the left ventral hippocampus
parative to regular diet (Fig. 2b), without any direct in 45-day-old rats. Paraffin 10 lm thick sections were stained
impact on nucleus or cytoplasm shape. On the with a combination of hematoxylin–eosin and indigo carmine;
contrary, postnatal thiamine deficiency exhibited sections of the midtemporal hippocampus were assessed. (a)
The arrowhead demarcates the CA3 region and the arrow
more cornered, irregular and sparse pyramidal cells
denotes the CA1 region; field CA4 is enclosed by broken lines;
in the hippocampal CA3 field (Fig. 2d), comparative bar = 100 lm. P: pyramidal cell layer; G: granule cell layer;
to regular diet (Fig. 2b). Figure 2d shows typical sm: stratum moleculare; sr: stratum radiatum; so: stratum
features of severe postnatal thiamine deficiency with oriens. (b–d) Effects of developmental thiamine deficiencies on
the hilar CA3 pyramidal cells of the hippocampus. (b) Controls;
characteristic breakings on cellular membranes illus-
(c) Prenatal exposed pups; (d) Postnatal exposed; bar = 20 lm
trated by more cornered than pyramidal shaped cells
in the hippocampal CA3 field. Moreover, postnatal condensed chromatin (Fig. 2d), (Kerr et al. 1994). It
thiamine deficiency resulted in a significant increase is obvious that prenatal thiamine deficiency kills cells
in pro-apoptotic-related morphological and biochem- metabolically, while postnatal thiamine deficiency
ical changes characterized by cells containing damages cells structurally.

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926 Cell Mol Neurobiol (2008) 28:923–931

How to interpret the specific and nonspecific (Navarro et al. 2005). However, the cause of Wer-
effects of thiamine lack on the developing CNS? nicke’s encephalopathy is thiamine deficiency as a
result of any nutritionally deficient state, and the
disease could not be confined only to alcoholics
Metabolic Role of Thiamine (Donnino et al. 2007). In addition, thiamine defi-
ciency induces quantitative, distinct inflammatory
Our studies indicate that specific and nonspecific responses and oxidative stress in vulnerable and
effects express two diametrically diverse functions of nonvulnerable regions that lead to cellular loss
thiamine in development (Fig. 1). The percentage of (Karuppagounder et al. 2007).
functions altered by the nonspecific effects of thia- Several basic mechanisms underlying thiamine
mine deficiency decreases from prenatal (60.14%) to deficiency-induced apoptosis and neurodegeneration
perinatal (35.31%) and postnatal periods (14.32%), have been reported recently. These mechanisms
(Bâ 2005); these periods overlap the moments of include: (i) Compromised energy production and
cellular migration, proliferation and developmental lactic acidosis (Martin et al. 2003; Navarro et al.
apoptosis that is active shortly after that (Bâ et al. 2005); (ii) excess levels of free radicals and oxidative
2005). Concomitantly, the rate of cellular death stress (Gibson and Blass 2007; Frank et al. 2008);
decreases progressively from prenatal (39.97%) to (iii) changes in microglia making a start on neuro-
perinatal (26.75%) and postnatal periods (14.92%), degeneration (Ke and Gibson 2004); (iv) the voltage-
(Fig. 1), (Bâ et al. 2005). Our present results con- dependent K + membrane conductance alteration
firmed a significant positive correlation between (Oliveira et al. 2007); (v) cellular membrane break-
cellular death and the nonspecific effects of develop- ing (Bâ et al. 1996); (vi) the mitochondrial caspase
mental thiamine deficiency. The nonspecific effects 3-mediated apoptosis (Chornyy et al. 2007); (vii)
would be assigned to the undernourishment that translocation of amyloid precursor protein C-terminal
comes with the thiamine deficiency. Consequently, fragments into the nucleus (Karuppagounder et al.
developmental thiamine deficiency-induced cellular 2008). Seemingly, most of these mechanisms are
death would be caused by the nonspecific effects of membrane-mediated effects of thiamine deficiency.
that deficiency, e.g., the malnutrition that comes with In addition, experimental thiamine deficiency is a
the vitamin lack (Bâ et al. 2005). The nonspecific model of impaired oxidative metabolism (Ke and
effects should be expressed by the metabolic role of Gibson 2004). Thiamine-dependent mitochondrial
thiamine. How thiamine (B1 vitamin) deficiency dehydrogenase complexes produce oxygen free
induces cellular death? radicals (Gibson and Blass 2007). Oxygen-dependent
To explain mechanisms of cellular damage and free radical is generated during substrate turnover in
death, most of investigations have focused on general the krebs cycle and its reaction with molecular
metabolic effects of thiamine deficiency like ultimate oxygen results in the continuous production of
actions of B1 vitamin lack. For instance, metabolic reactive oxygen species (ROS) under aerobic condi-
reduction of thiamine-dependent enzymes should be tions (Frank et al. 2008). Overproduction of ROS
the starting box of any peripheral and central neur- (arising from mitochondrial electron-transport chain)
opathies (Butterworth 1989). However, following results in oxidative stress which damages cellular
thiamine deficiency, thiamine-dependent enzymes, structures, including lipids and membranes, proteins,
i.e., a-ketoglutarate and pyruvate dehydrogenases and DNA (Valko et al. 2007). Indeed, thiamine can
complexes, as well as non-thiamine-dependent act as a free radical scavenger (Gibson and Blass
enzymes, i.e., succinate and malate dehydrogenases 2007). Free-radicals derive from mitochondrial
of the tricarboxylic acid cycle are reduced in the dysfunction (Mancuso et al. 2007). Alteration of
brains of mice (Bubber et al. 2004). Another example mitochondrial TPP transporter causes neural tube
is the Wernicke’s encephalopathy diagnosed in closure defect and results in Amish Lethal Micro-
chronic alcoholics, described as a constellation of cephaly (Lindhurst et al. 2006). Thiamine deficiency
selective neuropathological lesions occurring in the which provokes mitochondrial dysfunction with
brain of patients in which thiamine deficiency was increased glycolysis, increased lactate dehydrogenase
indexed as the causal factor of selective neuronal loss and focal lactate accumulation (Navarro et al. 2005),

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Cell Mol Neurobiol (2008) 28:923–931 927

results in a significant release of free radicals which, pH changes by focal lactate acidosis should be an
in turn, diminishes reduced glutathione (GSH) and endogenous factor to launch and/or to amplify the
other defense systems against oxidative stress at the cascade of cellular death pathways.
origin of major neurodegenerative diseases. For
instance, Prion diseases or Transmissible Spongiform
Encephalopathies (TSE) are connected with a con- Structural Role of Thiamine
genital and dramatic loss of antioxidant defense
proteins in the brain (Brown 2005). Another meta- Our results also indicate a negative correlation between
bolic disease related to thiamine and oxidatif stress is cellular death and the specific effects of thiamine
diabetes. Complications in diabetes mellitus are deficiency, which increase over postnatal days. These
partially mediated by enhanced formation of reactive observations suggest that specific effects bribe altera-
oxygen species (Schmid et al. 2008), similarly to tions in membrane processes which develop postnatally,
thiamine deficiency. Benfotiamine, a lipophilic e.g., cellular differentiation, synapses formation, axonal
derivative of thiamine with better bioavailability, growth, and myelinogenesis (Bâ 2005). In example, it
alleviates diabetes-induced cerebral oxidative stress appears in our studies that structural alterations consti-
(Wu and Ren 2006). Benfotiamine prevents oxidative tute the main effects of postnatal thiamine deficiency,
stress-induced DNA damage (Schmid et al. 2008) including more cornered, irregular and sparse pyramidal
and corrects defective replication in human umbilical cells in the hippocampal field CA3, comparative to
vein endothelial cells cultured in high glucose either regular diet or prenatal thiamine deficiency. These
(Pomero et al. 2001). The thiamine derivative pro- structural changes were accompanied by biochemical
drug prevents micro- and macrovascular endothelial modifications characterized by cells containing con-
dysfunction and the oxidative stress accompanying densed chromatin visible in Fig. 2d.
that dysfunction in type 2 diabetes (Stirban et al. Indeed, a number of experimental issues reveal
2006). Both thiamine and benfotiamine correct that thiamine interferes with the membrane structure
increased apoptosis due to high glucose in cultured and function, acts against agents-induced cytotoxicity
vascular cells (Beltramo et al. 2004). These observa- and highlight the presence of thiamine-binding sites
tions suggest that oxidative damage is critical to the on biological membranes.
pathogenesis of thiamine deficiency (Gibson and
Blass 2007). From the analysis of the implication of Membrane Structure and Function
B1 vitamin lack in different metabolic diseases, we
propose an integrated mechanism for the metaboli- The interference of thiamine with the structure and
cally thiamine deficiency-induced cellular death function of biological membrane becomes obvious.
which starts with extended free radicals damage in Some previous studies reported that thiamine would
the brain. Increased free radicals production related to be an active component of axoplasmic, mitochondrial
thiamine deficiency launch cellular membrane dam- (Tanaka and Cooper 1968; Itokawa et al. 1972) and
age, including lipoperoxydation (Bâ et al. 1999; synaptosomal membranes (Matsuda and Cooper
Valko et al. 2007), alteration of neuron ion channels 1981). It undergoes axonal anterograde transportation
and transporters and microglia changes. Persistent and retrograde as well (Tanaka et al. 1973; Bergquist
free radicals produced by severe thiamine deficiency and Hanson 1983), and intervenes in the synaptic
break cellular membrane (Bâ et al. 1996, 1999) transmission (Siegel et al. 1989). For instance, Thi-
which signals a cascade of cellular death pathways amine was reported to fix membrane ion channels and
via intracellular messengers, like intracellular caspase to modify their activity (Tallaksen and Tauboll 2000).
3-mediated apoptosis, toward the nucleus. Caspase 3 Thus, thiamine deficiency provoked a significant
had been identified among the first components of the decrease in the voltage-dependent K+ membrane
programmed cellular death machinery (Zakeri and conductance of cerebellar granule neurons, by sup-
Lockshin 2008). Subsequent nucleolysis machinery pression of A-type K+ channels mainly, that leads to
includes, among others, translocation of proteins neuronal cell damage and loss (Oliveira et al. 2007).
carboxy-terminal fragments into the nucleus of The consequence is the significant reduction of
neurons (Karuppagounder et al. 2008). The cytosolic nervous conduction speed (Goldberg et al. 2004),

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928 Cell Mol Neurobiol (2008) 28:923–931

followed by the blocking of the nervous fiber action Membrane Sites

potential by the pyrithiamine, an antagonist of the
thiamine (Goldberg and Cooper 1975). Thiamine There is an increasing argumentation reporting the
deficiency should provoke further disturbances in existence of thiamine-binding sites on biological
nervous electrical activities by the alteration of membranes (thiamine triphosphate) different from its
myelinogenesis (Trostler et al. 1977; Reddy and membrane carrier sites (thiamine diphosphate). Con-
Ramakrishnan 1982), resulting in reduction of the trary to the thiamine triphosphate (TTP) that fixes on
diameter of myelinic fibers (Claus et al. 1985). the cellular surface, thiamine diphosphate (TDP) was
fixed by a specific intra membrane carrier and
Membrane Stability transported into the cytosol actively (Spector and
Johanson 2007). The first allusion to the existence of
It seems obvious that thiamine exerts stabilizing thiamine-binding sites on biological membranes,
interactions on the biological membranes. Investiga- different from intra membrane carrier, was suggested
tions on the role of thiamine during developmental trough the reversal of the effects of thiamine
processes confirm physiologic protecting actions of deficiency by antioxidants, suggesting that thiamine
thiamine on nervous cells and others tissues. For may act as a site-directed antioxidant (Gibson and
instance, thiamine stabilizes the membrane of newly Zhang 2002). Recent disclosure in peroxisomes of
generated neuronal cells during embryogenesis and TDP-dependent enzyme that catalyzes alpha-oxida-
slows the programmed cell death that is the devel- tion of straight chain fatty acids makes possible the
opmental apoptosis (Wang et al. 2000; Bâ et al. existence of membrane surface sites fixing thiamine
2005). In addition, the study on differential altera- (Sniekers et al. 2006; Fraccascia et al. 2007).
tions in the distribution of three phosphatase Through our developmental studies, we reported that
enzymes, during early pregnancy in the rat, has the specific need of B1 vitamin increased in nervous
shown that thiamine contributes to the process of tissues during ontogenesis and corresponded to the
plasma membrane transformation of uterine epithelial post-natal development of membrane processes (Bâ
cells (Bucci and Murphy 1999). However, most of the 2005). An assumption is that the developing mem-
studies highlight the capacity of thiamine to protect branes should generate an increasing surface
cellular membrane against alcohol-induced cytotoxic distribution of thiamine-binding sites insuring their
effects. Thus, thiamine prevents or reduces alcohol- stability. That assumption was corroborated by
induced damages of hippocampal CA1 pyramidal previous studies reporting changes of thiamine
cells in rat CNS (Wenisch et al. 1996). In addition, metabolism in the rat brain during postnatal devel-
pyrithiamine and ethanol-induced cytotoxicity is opment (Matsuda et al. 1989). Indeed, from birth to
prevented in cerebellar slice cultures co-exposed to 3 weeks, the activity of thiamine diphosphatase
thiamine (Mulholland et al. 2005). For the former (TDPase) developped more strongly in the liver than
explanations of the observed alcohol-thiamine antag- in the brain, while that of thiamine triphosphatase
onism on cytotoxicity, Bâ et al. (1996) hypothesized (TTPase) increased more powerfully in the brain than
that B1 vitamin acts against the effects of ethanol on in the liver (Matsuda et al. 1989). Thus, microsomal
fluidity, and therefore increases membrane stability and soluble TTPase in the cerebral cortex and
(Bâ et al. 1996). To explain the mechanisms of action cerebellum increased after birth and plateaued at
on biological membranes, thiamine was suggested to 3 weeks; the increase of the enzyme activity was
exert a nonspecific stabilizing interaction on the more significant in the former tissue than in the latter
axonal membrane (Goldberg et al. 2004). However, a (Matsuda et al. 1989). These observations suggest
recent study has reported the specificity of vitamin that in the nervous tissue, TTPase activity should
B1, and not B6 or B12, in protecting cardiac interfere with the post-natal development of mem-
ventricular myocytes against the effects of alcohol brane processes. Makarchikov et al. (2003) reported
metabolite, the acetaldehyde-induced cytotoxicity that TTP was widely distributed from prokaryotes to
and apoptotic cell death (Aberle et al. 2004). The mammals and may have a basic role in cell metab-
last hypothesis states the problem of the existence of olism or cell signaling. For instance, the main electric
thiamine-binding sites on biological membranes. organ of Electrophorus electricus is particularly rich

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Cell Mol Neurobiol (2008) 28:923–931 929

in TTP, which represents 87% of the total thiamine show any significant correlation neither with nonspe-
content in this tissue (Bettendorff et al. 1987). Such cific, or specific effects of developmental thiamine
an observation suggests TTPase implication in the deficiency. These results indicate that the lack of
restoration of membrane stability after intense elec- thiamine is not a causative factor of cellular atrophy.
trical activity. Thus, TTP seems to be essentially Thus, thiamine cannot be classified like a growth
associated with neurons: In rat brain, the amount of factor. In recent studies, determination of the impact
TTP is about five times higher in neurons than in of the dietary concentration of 5 B vitamins (ribofla-
astrocytes (Bettendorff et al. 1991). Indeed, the vin, niacin, pantothenic acid, cobalamin, and folacin)
membrane-associated enzyme form (TTPase) may showed no influence on pig growth performance; the
play a physiologic role other than TTP hydrolysis in greater need for these vitamins is not associated with
mammalian tissues (Szyniarowski et al. 2005). In greater dietary energy intake or body energy accre-
vertebrate tissues, TTPase may act as a phosphate tion rate, but is potentially due to shifts in the
donor for the phosphorylation of certain proteins; that predominant metabolic pathways (Stahly et al. 2007;
may be part of a new signal transduction pathway Böhmer and Roth-Maier 2007).
(Czerniecki et al. 2004). Thiamine deficiency
decreases membrane-associated TTPase activity
(Iwata et al. 1974). Membrane-associated TTPase is
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