Modeles experimentaux d’etude de L’homocysteine
II. MODELES NUTRITIONNELS
4. Modèles Folbp1 +/- et Folbp1 -/-
Spigelstein et al 2002, ont mis en place un modèle de souris transgéniques Folbp1 -/- .
L’absence de cette protéine impliquée dans le transport de l’acide folique présente des conséquences morphologiques sévères chez le foetus, entraînant la mort in utero.
Ces embryons présentent des anomalies sévères de fermeture du tube neural, ainsi que des malformations cranio-faciales telles que les fentes labio-maxillo-palatines. [319]
Les embrayons Folbp1 +/- hétérozygotes ne présentent pas d’anomalies morphologiques aussi sévère que chez les homozygotes, une grande partie des embrayons sont phénotypiquement non différents des embrayons sauvages. [319]
116
117
On peut donc conclure que :
La méthionine est un acide aminé soufré essentiel utilisée pour la synthèse de l’adénosyl-méthionine, c’est le principal donneur de groupements méthyles nécessaires à la méthylation de l’ADN, l’ARN, des protéines et des lipides. L’homocystéine est un acide aminé dérivé du métabolisme de la méthionine, qui
n’est pas incorporé dans les protéines. Elle peut être métabolisée par 2 voix : la voix de la transsulfuration, conduisant à la formation de cystéine, et la voix de reméthylation en méthionine.
Le métabolisme de l’homocystéine est dépendant de l’apport en plusieurs facteurs vitaminiques : vitamines B6 et B12, acide folique.
Les hyperhomocystéinémies peuvent être provoquées par des anomalies soit de la transsulfuration, soit de la reméthylation. Leur cause peut être soit génétique (déficits enzymatiques), soit environnementale ou bien nutritionnelles (carences vitaminiques).
L’exploration du métabolisme de l’homocystéine comporte, outre le dosage de l’homocystéine circulante totale, des dosages de vitamines, un test de charge en méthionine, le dépistage de mutations des gènes codant les enzymes impliquées. La mutation associée aux hyperhomocystéinémies modérées, la plus recherchée en pratique courante, est celle du gène de la MTHFR en position 677.
L’Hyperhomocystéinémie et la déficience en folates constitue un facteur de risque de diverses pathologies cardiovasculaires, intestinales et neurodégénératives, parmi lesquelles les accidents vasculaires cérébraux, la maladie d’Alzheimer et la maladie de Parkinson, ainsi que les risques d’avortement spontané, la carence en folates chez la femme enceinte constitue un facteur de risque de plusieurs malformations congénitales chez le nouveau-né, particulièrement Le spina-bifida
118
119
RESUME
Titre : Les troubles du métabolisme de la méthionine Auteur : Nadia OUKNOUZ
Rapporteur : Professeur Saïda TELLAL
Mots-clés : méthionine, homocystéine, folates, cobalamine, cystathionine-β synthase,
Méthylène-tétrahydrofolate-réductase
La méthionine est un acide aminé soufré essentiel utilisée pour la synthèse de l’adénosyl-méthionine, coenzyme donneur de méthyl des méthyltransférases. Cette transméthylation libère l’homocystéine, qui peut être catabolisée selon deux voies métaboliques : la reméthylation et la transulfuration.
En cas d’apport protéique excessif, la voie de la transulfuration est favorisée par rétrocontrôle positif de la cystathionine bêta-synthase et rétro-contrôle négatif de la 5, 10-méthylènetétrahydrofolate réductase, le régulateur allostérique étant la S-adénosyl-méthionine. Dans ce cas, la cystéine formée à partir de l’Hcy est incorporée dans le glutathion ou convertie en sulfates qui sont excrétés dans les urines. A l’inverse, en cas de déficit protéique, la voie de la reméthylation est favorisée et l’Hcy est recyclée en méthionine.
La méthylcobalamine, la forme méthylée de la vitamine B12, est indispensable à l’activation de la méthionine synthase, enzyme dépendante du cycle des folates et nécessaire à la synthèse de la méthionine à partir de l’homocystéine.
Des études épidémiologiques et expérimentales ont établi un lien entre une hyperhomocystéinémie, la déficience en folates et diverses pathologies cardiovasculaires, intestinales et neurodégénératives, parmi lesquelles les accidents vasculaires cérébraux, la maladie d’Alzheimer et la maladie de Parkinson. Outre les risques d’avortement spontané, la carence en folates chez la femme enceinte constitue un facteur de risque de plusieurs malformations congénitales chez le nouveau-né, particulièrement Le spina-bifida.
Bien que l’homocystéine soit conditionnée par les facteurs génétiques, environnementaux et nutritionnels, la part de chacun d’entre eux est difficile à déterminer dans l’hyperhomocystéinémie observé en pathologie, Différentes investigations biologiques en permettent un diagnostic de plus en plus fin. Les diverses carences vitaminiques génératrices d’hyperhomocystéinémie suggèrent la possibilité d’une prise en charge thérapeutique effective.
120
SUMMARY
TITLE: Metabolic disorders of methionine AUTHOR: NADIA OUKNOUZ
DOCTORAL SUPERVISOR: Professor Saïda TELLAL
KEYS WORDS: Methionine, homocysteine, folates, cobalamin, cystathionine-β synthase,
methylene-tetrahydrofolate-reductase
Methionine is an essential sulphur amino acid used for the synthesis of adenosil-methionine, coenzyme donor of methyl of methyltransferase. This transmethulation liberates homocysteine, which can be catabolized by two metabolic pathways: the pathway of remethylation and transulfurization.
In the case of excessive protein intake, the transulfurization pathway is favoured by positive retrocontrol of beta-synthase cystathionine and negative retro-control of 5, 10-methylenetetrahydrofolate reductase, the allosteric regulator being S-adenosil-methionine. In this case, cysteine formed from Hcy is incorporated into glutathione or converted into sulphates which are excreted in the urine. Conversely, in case of protein deficiency, the route of remethylation is favoured and Hcy is recycled into methionine.
Methylcobalamin, the methylated form of vitamin B12, is essential for the activation of methionine synthase, an enzyme dependent on the folate cycle and necessary for the synthesis of methionine from homocysteine.
Epidemiological and experimental studies have established a link between hyperhomocysteinemia, deficiency in folates and various cardiovascular, intestinal and neurodegenerative pathologies, including stroke, Alzheimer’s disease and Parkinson’s disease. In addition to the risk of spontaneous abortion, folate deficiency in pregnant women is a risk factor for several birth defects in newborns, particularly spina bifida.
Although homocysteine is conditioned by genetic, environmental and nutritional factors, the share of each is difficult to determine in the hyperhomocysteinemia observed in pathology, various biological investigations allow for an increasingly refined diagnosis. The various vitamin deficiencies generating hyperhomocysteinemia suggest the possibility of effective therapeutic management.
121
.
ﺺ ﳌا
ناﻮﻨﻌﻟا
:ن ﻧﻮﻴﺜﳌا ﺾﻳأ تﺎﺑاﺮﻄﺿا
ﻒﻟﺆﳌا
:
زﻮﻨﻛأ ﺔﻳدﺎﻧ
فﺮﺸﳌا
:
لﻼﻃ ةﺪﻴﻌﺳ ةذﺎﺘﺳ
ﺔﻴﺳﺎﺳ تﺎﻤﻠ ﻟا
: ن ﻧﻮﻴﺜﳌاﻣو ،
ن ﻧﻮﻳﺎﺘﺴ ﺴﻟا ،ن ﳌﺎ ﻮ ﻟا ،تﻻﻮﻔﻟا ،ن ﻴ ﺴ ﺳﻮ
-ن ﻠﺘﻴﻣو ،زﺎﺘﻧﺎﺳ ﺎﺘ ﺑ
-ﻲ ﻼﺛ
ﻟا
تﻻﻮﻓورﺪﻴ
–
ﺔﻟ ﺨﻣ
.
ﺾﻤﺣ ﻮ ن ﻧﻮﻴﺜﳌا
ﺖﻳ ﻜﻟا ﻋ يﻮﺘﺤﻳ ﺎﺳأ ﻴﻣأ
،
ن ﻧﻮﻴﺜﻣ ﻞﻴﺳﻮﻧد ﺐﻴﻛ ﻟ مﺪﺨﺘﺴ ُ
،
ﻞﻘﻧ ﺢﻧﺎﻣ ﻢ ﺰﻧإﻮ
ﻞﻴ ﻴﳌا
ﻞﻴ ﻴﳌا ﻞﻘﻧ ﺴ ﺔﻴﻠﻤﻌﻟا ﻩﺬ ،
رﺮﺤﺗ ﻟاو ،
ن ﻴ ﺴ ﺳﻮﻣو
،
ن ﻴﻀﻳأ ﻦ رﺎﺴﳌ ﻊﻀﺨﻳ نأ ﻦﻜﻤﻳ يﺬﻟا
:
.ﺪﻴﻤﻀﺘﻟاو ﻞﻴﺛ ةدﺎﻋإ رﺎﺴﻣ
ن ﺗو ﻟا لوﺎﻨﺗ طاﺮﻓ ﺔﻟﺎﺣ
ﺎﺘ ﺑ ﺾﻔﺧ ﻲ ﺎﺠﻳ ﻢﻜﺤﺘﻟا ﻖ ﺮﻃ ﻦﻋ ﺪﻴﻤﻀﺘﻟا رﺎﺴﻣ ﻞﻴﻌﻔﺗ ﻢﺘﻳ ،
-ﺟﺮﻟا ﻠﺴﻟا ﻢﻜﺤﺘﻟاو ،زﺎﺘﻧﺎﺳ ن ﻧﻮﻳﺎﺗﺎﺘﺴ ﺳ
5
،
10
ﻞﻴ ﻴﻣ
-ﳌا ،تﻻﻮﻓورﺪﻴ ﻟا ﻲ ﻼﺛ
ﻞﻴﺳﻮﻧد ﻮ ﻲ ا ﺴﻟا ﻢﻈﻨ
تﺎﺘﻳ ﻛ إ ﺎ ﻠ ﻮﺤﺗ وأ نﻮﻴﺛﺎﺗﻮﻠ ا ن ﻴ ﺴ ﺳﻮﻣو ﻦﻣ ﺖﻠ ﺸ ﻟا ن ﺘﺴ ﺴﻟا ﺞﻣد ﻢﺘﻳ ،ﺔﻟﺎ ا ﻩﺬ . ن ﻧﻮﻴﺜﻣ
إ ن ﻴ ﺴ ﺳﻮﻣو ﺮ وﺪﺗ دﺎﻌ ُ و ﻞﻴ ﻳإ ةدﺎﻋإ رﺎﺴﻣ ﻞﻴﻌﻔﺗ ﻢﺘﻳ ،ن ﺗو ﻟا ﺺﻘﻧ ﺔﻟﺎﺣ ﺎﻣا،لﻮﺒﻟا ﺎ زاﺮﻓإ ﻢﺘﻳ
.ن ﻧﻮﻴﺜﳌا
ﺘﻌ و
ن ﻣﺎﺘﻴﻓ ﻦﻣ ﻴ ﻴﳌا ﻞ ﺸﻟا
B12
ﺎﺳﺎﺳا ﺪﻤﺘﻌ ﻟاو ،زﺎﺘﻧﺎﺳ ن ﻧﻮﺜﻴﳌا ﻢ ﺰﻧأ ﻂﻴﺸ ﺘﻟ ﺎﻴﺳﺎﺳأ
ﻋ
ن ﻣﺎﺘﻔﻟا
B9
ن ﻴ ﺴ ﺳﻮﻣو ﻦﻣ ﺎﻗﻼﻄﻧا ن ﻧﻮﺜﻴﳌا ﺐﻴﻛ ﻟ ﺔ روﺮﺿ ﺎ أ ﺎﻤﻛ
ﻦﻣ ﺪﻳﺪﻌﻟاو مﺪﻟا ن ﻴ ﺴ ﺳﻮﻣو ﺔﻤﻴﻗ ﺺﻘﻧ ن ﺑ ﺔﻠﺻ دﻮﺟو ﺔﻴ ﺮﺠﺘﻟاو ﺔﻴﺋﺎ ﻮﻟا تﺎﺳارﺪﻟا ﺖ ﺒﺛأ ﺪﻗو
ضاﺮﻣ
نﻮﺴ ﻛرﺎﺑ ضﺮﻣو ،ﺮﻤﻳﺎ ﺰﻟا ضﺮﻣو ،ﺔﻴﻏﺎﻣﺪﻟا ﺔﺘﻜﺴﻟا ﻚﻟذ ﺎﻤﺑ ،ﺔﻴ ﺼﻌﻟاو ﺔ ﻮﻌﳌاو ﺔﻴﺋﺎﻋﻮﻟا ﺔﻴﺒﻠﻘﻟا
ﺔﻓﺎﺿﻹﺎ و ،
ن ﻣﺎﺘﻔﻟا ةدﺎﻣ ﺺﻘﻧ نﺈﻓ ،ﻲ ﺎﻘﻠﺘﻟا ضﺎ ﺟ ﺮﻄﺧ إ
B9
ﺪﻴﻟاﻮﳌا ﺔﻴﻘﻠﺧ بﻮﻴﻋ ةﺪﻌﻟ ﺮﻄﺧ ﻞﻣﺎﻋ ﻮ ﻞﻣاﻮ ا ىﺪﻟ
.اﺪﻴﻔﻴﺑ ﺎﻨ ﺒﺳ ﺔﺻﺎﺧ ،دﺪ ا
ﻣ ﻢﻏﺮﻟا ﻋ
ﻞﻣاﻮﻋ ةﺪﻋ دﻮﺟو ﻦ
،
ﺔﻴﺋاﺬﻏو ﺔﻴ ﻴ و ﺔﻴﺛارو
،
مﺪﻟا ن ﻴ ﺴ ﺳﻮﻣو ﺔﺒﺴ عﺎﻔﺗرا ﻞﺧﺪﺘﺗ
،
ﻻإ
ﮫﻧأ
ضﺮﳌا ﺔﻟﺎﺣ ﺐ ﺴﻟا ﺎ ﻣ يأ ﺪﻳﺪﺤﺗ ﺐﻌﺼﻳ
،
ﺢﻤﺴ ﺔﻘﻴﻗﺪﻟا ﺔﻴﺟﻮﻟﻮﻴﺒﻟا تﺎﻘﻴﻘﺤﺘﻟا ﻦﻣ ﺪﻳﺪﻌﻟا نأ ﻻإ
ﺺﻴ ﻟﺎﺑ
عاﻮﻧأ ﻊﻴﻤﺟ رﺎﺒﺘﻋ ن ﻌ ﺪﺧ ﺐﺠﻳ ﺎﻤﻛ .
تا ﺼﻘﺘﻟا
ﻴﻔﻟا
طﺮﻓ ﺪﻟﻮﺗ ﻟا ﺔﻔﻠﺘﺨﳌا تﺎﻨﻴﻣﺎﺘ
مﺪﻟا ن ﻴ ﺴ ﺳﻮﻣو
.
122
123
[1] Halsted CH1, Villanueva JA, Devlin AM, Niemelä O, Parkkila S, Garrow TA et al.
Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig. Proc Natl Acad Sci U S A. 2002 .99(15): 10072-7.
[2] Selhub J. Homocysteine metabolism. Annu Rev Nutr. 1999; 19:217-46.
[3] Yang, M., and Vousden, K.H. (2016). Serine and one-carbon metabolism in cancer. Nature
reviews Cancer 16, 650-662.
[4] Sunden SL, Renduchintala MS, Park EI, Miklasz SD, Garrow TA (1997)
Betaine-homocysteine methyltransferase expression in porcine and human tissues and chromosomal localization of the human gene. Arch Biochem Biophys 345:171-174.
[5] Chamberlin ME, Ubagai T, Mudd SH, Thomas J, Pao VY, Nguyen TK, Levy HL, Greene C, Freehauf C, Chou JY (2000) Methionine adenosyltransferase I/III deficiency:
novel mutations and clinical variations. Am J Hum Genet 66:347-355.
[6] Janosik M, Kery V, Gaustadnes M, Maclean KN, Kraus JP (2001) Regulation of human
cystathionine beta-synthase by S-adenosyl-L-methionine: evidence for two catalytically active conformations involving an autoinhibitory domain in the C-terminal region. Biochemistry 40:10625-10633.
[7] Oltean S, Banerjee R (2003) Nutritional modulation of gene expression and homocysteine
utilization by vitamin B12. J Biol Chem 278:20778-20784.
[8] Chen HP, Marsh EN (1997) How enzymes control the reactivity of adenosylcobalamin:
effect on coenzyme binding and catalysis of mutations in the conserved histidine-aspartate pair of glutamate mutase. Biochemistry 36:7884-7889.
[9] Matthews PM (2001) Editorial commentary to Narayanan et al. Axonal metabolic recovery
in multiple sclerosis patients treated with interferon beta-1b. J Neurol 248:987.
[10] Mato JM, Alvarez L, Ortiz P, Pajares MA (1997) S-adenosylmethionine synthesis:
molecular mechanisms and clinical implications. Pharmacol Ther 73:265-280.
[11] Kutzbach C, Stokstad EL (1971) Mammalian methylenetetrahydrofolate reductase. Partial
purification, properties, and inhibition by S-adenosylmethionine. Biochim Biophys Acta 250:459-477.
124
[12] Finkelstein JD (1998) The metabolism of homocysteine: pathways and regulation. Eur J
Pediatr 157 Suppl 2:S40- 44.
[13] Huang G, Dragan M, Freeman D, Wilson JX (2005) Activation of
catechol-O-methyltransferase in astrocytes stimulates homocysteine synthesis and export to neurons. Glia 51:47-55.
[14] Cornell, K.A., Winter, R.W., Tower, P.A., and Riscoe, M.K. (1996). Affinity purification
of 5-methylthioribose kinase and 5-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Klebsiella pneumoniae [corrected]. The Biochemical journal 317 ( Pt 1), 285-290.
[15] Thomas, D., Becker, A., and Surdin-Kerjan, Y. (2000). Reverse methionine biosynthesis
from S-adenosylmethionine in eukaryotic cells. J Biol Chem 275, 40718-40724.
[16] Backlund, P.S., Jr., and Smith, R.A. (1981). Methionine synthesis from
5'-methylthioadenosine in rat liver. J Biol Chem 256, 1533-1535.
[17] Backlund, P.S., Jr., Chang, C.P., and Smith, R.A. (1982). Identification of
2-keto-4-methylthiobutyrate as an intermediate compound in methionine synthesis from 5'-methylthioadenosine. J Biol Chem 257, 4196-4202.
[18] Trackman, P.C., and Abeles, R.H. (1983). Methionine synthesis from
5'-S-Methylthioadenosine. Resolution of enzyme activities and identification of 1-phospho-5-S methylthioribulose. J Biol Chem 258, 6717-6720.
[19] Batova, A., Diccianni, M.B., Omura-Minamisawa, M., Yu, J., Carrera, C.J., Bridgeman, L.J., Kung, F.H., Pullen, J., Amylon, M.D., and Yu, A.L. (1999). Use of
alanosine as a methylthioadenosine phosphorylase-selective therapy for T-cell acute lymphoblastic leukemia in vitro. Cancer research 59, 1492-1497.
[20] Tang, B., Li, Y.N., and Kruger, W.D. (2000a). Defects in methylthioadenosine
phosphorylase are associated with but not responsible for methionine-dependent tumor cell growth. Cancer research 60, 5543-5547.
[21] Kubota, M., Kamatani, N., and Carson, D.A. (1983). Biochemical genetic analysis of the
role of methylthioadenosine phosphorylase in a murine lymphoid cell line. J Biol Chem 258, 7288-7291.
125
[22] Tisdale, M.J. (1983). Methionine synthesis from 5'-methylthioadenosine by tumour cells.
Biochemical pharmacology 32, 2915-2920.
[23] Dykstra, W.G., Jr., and Herbst, E.J. (1965). Spermidine in Regenerating Liver: Relation
to Rapid Synthesis of Ribonucleic Acid. Science 149, 428-429.
[24] Fillingame, R.H., and Morris, D.R. (1973). Polyamine accumulation during lymphocyte
transformation and its relation to the synthesis, processing, and accumulation of ribonucleic acid. Biochemistry 12, 4479-4487.
[25] Hoffman, R.M. (1985). Altered methionine metabolism and transmethylation in cancer.
Anticancer research 5, 1-30.
[26] Wagner, C., Decha-Umphai, W., and Corbin, J. (1989). Phosphorylation modulates the
activity of glycine N-methyltransferase, a folate binding protein. In vitro phosphorylation is inhibited by the natural folate ligand. J Biol Chem 264, 9638-9642.
[27] Hirata, F., Toyoshima, S., Axelrod, J., and Waxdal, M.J. (1980). Phospholipid
methylation: a biochemical signal modulating lymphocyte mitogenesis. Proc Natl Acad Sci U S A 77, 862-865.
[28] Hoffman, D.R., Cornatzer, W.E., and Duerre, J.A. (1979). Relationship between tissue
levels of S-adenosylmethionine, S-adenylhomocysteine, and transmethylation reactions. Canadian journal of biochemistry 57, 56-65.
[29] Kredich, N.M., and Hershfield, M.S. (1979). S-adenosylhomocysteine toxicity in normal
and adenosine kinase-deficient lymphoblasts of human origin. Proc Natl Acad Sci U S A 76, 2450-2454.
[30] Kredich, N.M., and Martin, D.V., Jr. (1977). Role of S-adenosylhomocysteine in
adenosinemediated toxicity in cultured mouse T lymphoma cells. Cell 12, 931-938.
[31] Dante, R., Arnaud, M., and Niveleau, A. (1983). Effects of
5'deoxy-5'-methylthioadenosine on the metabolism of S-adenosyl methionine. Biochemical and biophysical research communications 114, 214-221.
[32] Ferro, A.J., Vandenbark, A.A., and MacDonald, M.R. (1981). Inactivation of
S-adenosylhomocysteine hydrolase by 5'-deoxy-5'-methylthioadenosine. Biochemical and biophysical research communications 100, 523-531.
126
[33] Fox, I.H., Palella, T.D., Thompson, D., and Herring, C. (1982). Adenosine metabolism:
modification by S-adenosylhomocysteine and 5'-methylthioadenosine. Archives of biochemistry and biophysics 215, 302-308.
[34] Williams-Ashman, H.G., Seidenfeld, J., and Galletti, P. (1982). Trends in the biochemical
pharmacology of 5'-deoxy-5'-methylthioadenosine. Biochemical pharmacology 31, 277-288.
[35] Matthews, J.H. (1998). The cytotoxic effect of the vitamin B12 inhibitor cyanocobalamin
[c-lactam], and a review of other vitamin B12 antagonists. Leukemia & lymphoma 31, 21-37.
[36] Olteanu, H., and Banerjee, R. (2001). Human methionine synthase reductase, a soluble
P-450 reductase-like dual flavoprotein, is sufficient for NADPH-dependent methionine synthase activation. J Biol Chem 276, 35558-35563.
[37] Leclerc, D., Wilson, A., Dumas, R., Gafuik, C., Song, D., Watkins, D., Heng, H.H., Rommens, J.M., Scherer, S.W., Rosenblatt, D.S., et al. (1998). Cloning and mapping of a
cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc Natl Acad Sci U S A 95, 3059-3064.
[38] Gulati, S., Brody, L.C., and Banerjee, R. (1999). Posttranscriptional regulation of
mammalian methionine synthase by B12. Biochemical and biophysical research communications 259, 436-442.
[39] Chen, Z., and Banerjee, R. (1998). Purification of soluble cytochrome b5 as a component
of the reductive activation of porcine methionine synthase. J Biol Chem 273, 26248-26255.
[40] Billings, R.E., Noker, P.E., and Tephly, T.R. (1981). The role of methionine in regulating
folate-dependent reactions in isolated rat hepatocytes. Archives of biochemistry and biophysics 208, 108-120.
[41] Kenyon, S.H., Nicolaou, A., Ast, T., and Gibbons, W.A. (1996). Stimulation in vitro of
vitamin B12-dependent methionine synthase by polyamines. The Biochemical journal 316 ( Pt 2), 661-665.
[42] Christopher, S.A., Diegelman, P., Porter, C.W., and Kruger, W.D. (2002).
Methylthioadenosine phosphorylase, a gene frequently codeleted with p16(cdkN2a/ARF), acts as a tumor suppressor in a breast cancer cell line. Cancer research 62, 6639-6644.
127
[43] Subhi, A.L., Diegelman, P., Porter, C.W., Tang, B., Lu, Z.J., Markham, G.D., and Kruger, W.D. (2003). Methylthioadenosine phosphorylase regulates ornithine decarboxylase by production of downstream metabolites. J Biol Chem 278, 49868-49873.
[44] Auvinen, M., Paasinen, A., Andersson, L.C., and Holtta, E. (1992). Ornithine
decarboxylase activity is critical for cell transformation. Nature 360, 355-358.
[45] Gupta, R., Hamasaki-Katagiri, N., White Tabor, C., and Tabor, H. (2001). Effect of
spermidine on the in vivo degradation of ornithine decarboxylase in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 98, 10620-10623.
[46] Grzelakowska-Sztabert, B., and Landman-Balinska, M. (1976). Regulation of
methionine synthetase in L-cells by vitamin B-12, folate and methionine. Biochemical Society transactions 4, 922-925.
[47] Tautt, J.W., Anuszewska, E.L., and Koziorowska, J.H. (1982). Methionine regulation of
N-5-methyltetrahydrofolate: homocysteine methyltransferase and its influence on the growth and protein synthesis in normal, neoplastic, and transformed cells in culture. Journal of the National Cancer Institute 69, 9-14.
[48] Kamely, D., Littlefield, J.W., and Erbe, R.W. (1973). Regulation of
5-methyltetrahydrofolate: homocysteine methyltransferase activity by methionine, vitamin B12, and folate in cultured baby hamster kidney cells. Proc Natl Acad Sci U S A 70, 2585-2589.
[49] Demuth, K., Atger, V., Borderie, D., Benoit, M.O., Sauvaget, D., Lotersztajn, S., and Moatti, N. (1999). Homocysteine decreases endothelin-1 production by cultured human
endothelial cells. European journal of biochemistry 263, 367-376.
[50] Gueant, J.L., Gueant-Rodriguez, R.M., Anello, G., Bosco, P., Brunaud, L., Romano, C., Ferri, R., Romano, A., Candito, M., and Namour, B. (2003). Genetic determinants of
folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome? Clinical chemistry and laboratory medicine 41, 1473-1477.
[51] Harding, C.O., Arnold, G., Barness, L.A., Wolff, J.A., and Rosenblatt, D.S. (1997).
Functional methionine synthase deficiency due to cblG disorder: a report of two patients and a review. American journal of medical genetics 71, 384-390.
128
[52] Watkins, D., and Rosenblatt, D.S. (1989). Functional methionine synthase deficiency (cblE
and cblG): clinical and biochemical heterogeneity. American journal of medical genetics 34, 427-434.
[53] McCully KS, Wilson RB (1975) Homocysteine theory of arteriosclerosis. Atherosclerosis
22:215-227.
[54] Butz LW, du Vigneaud V. The formation of a homologue of cystine by the decomposition
of methionine with sulfuric acid. J Biol Chem 1932; 99: 135-42.
[55] Mudd SH, Finkelstein JD, Refsum H, Ueland PM, Malinow MR, Lentz SR, Jacobsen DW, Brattstrom L, Wilcken B, Wilcken DE, Blom HJ, Stabler SP, Allen RH, Selhub J, Rosenberg IH (2000) Homocysteine and its disulfide derivatives: a suggested consensus
terminology. Arterioscler Thromb Vasc Biol 20:1704-1706.
[56] Jakubowski H (2006) Pathophysiological consequences of homocysteine excess. J Nutr
136:1741S-1749S.
[57] Ueland PM, Refsum H, Stabler SP, Malinow MR, Andersson A, Allen RH. Total
homocysteine in plasma or serum: methods and clinical applications. Clin Chem 1993; 39: 1764-79.
[58] Stipanuk MH, Ueki I. Dealing with methionine/homocysteine sulfur: cysteine metabolism
to taurine and inorganic sulfur. J Inherit Metab Dis. 2011 Feb;34(1):17-32. PubMed PMID: 20162368; PubMed Central PMCID: PMC2901774.
[59] Ueland PM, Refsum H, Brattström L. Plasma homocysteine and cardiovascular disease.
In: Francis Jr RB Ed.Atherosclerotic cardiovascular disease 1992. Marcel Dekker, Inc. hemostasis, and endothelial function. New York, 183-236.
[60] Ueland PM, Refsum H (1989) Plasma homocysteine, a risk factor for vascular disease:
plasma levels in health, disease, and drug therapy. J Lab Clin Med 114:473-501.
[61] Hultberg B, Berglund M, Andersson A, Frank A (1993) Elevated plasma homocysteine in
alcoholics. Alcohol Clin Exp Res 17:687-689.
[62] Cravo ML, Camilo ME (2000) Hyperhomocysteinemia in chronic alcoholism: relations to
129
[63] Barak AJ, Beckenhauer HC (1988) The influence of ethanol on hepatic transmethylation.
Alcohol Alcohol 23:73-77.
[64] Barak AJ, Tuma DJ, Beckenhauer HC (1985) Ethanol, the choline requirement,
methylation and liver injury. Life Sci 37:789-791.
[65] Cravo ML, Gloria LM, Selhub J, Nadeau MR, Camilo ME, Resende MP, Cardoso JN, Leitao CN, Mira FC (1996) Hyperhomocysteinemia in chronic alcoholism:
[66] Kenyon SH, Nicolaou A, Gibbons WA (1998) The effect of ethanol and its metabolites
upon methionine synthase activity in vitro. Alcohol 15:305-309.
[67] Mann NJ, Li D, Sinclair AJ, Dudman NP, Guo XW, Elsworth GR, Wilson AK, Kelly FD (1999) The effect of diet on plasma homocysteine concentrations in healthy male
subjects. Eur J Clin Nutr 53:895-899.
[68] Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J (1988)
Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatographymass spectrometry. J Clin Invest 81:466-474.
[69] Namour F, Helfer AC, Quadros EV, Alberto JM, Bibi HM, Orning L, Rosenblatt DS, Jean-Louis G (2003) Transcobalamin deficiency due to activation of an intra exonic cryptic
splice site. Br J Haematol 123:915-920.
[70] Chanarin I, Deacon R, Lumb M, Perry J. Cobalamin-folate interaction. Blood Rev 1990;3:
211-215
[71] Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J (2001)
Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 73:613-621.
[72] Hustad S, Ueland PM, Vollset SE, Zhang Y, Bjorke-Monsen AL, Schneede J (2000)
Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clin Chem 46:1065-1071.
[73] Rébeillé F, Ravanel S, Jabrin S, Douce R, Storozhenko S, Van Der Straeten D. Folates
in plants: Biosynthesis, distribution, and enhancement. Physiol Plant. 2006. 126(3):330 - 342
[74] Guéant JL, Namour F, Guéant-Rodriguez RM, Daval JL. Folate and fetal programming:
130
[75] Stea TH, Johansson M, Jägerstad M, Frølich W. Retentionof folates incooked, stored
andreheated peas, broccoli and potatoes for use in modern large scale service systems. Food Chem. 2007. 101(3), 1095–1107
[76] McDowell, LR. Vitamins in Animal Nutrition: Comparative Aspects to Human Nutrition.
Academic Press, San Diego, California. 2000.
[77] Smulders YM, Stehouwer CD. Folate metabolism and cardiovascular disease. Semin Vasc
Med. 2005. 5(2): 87-97.
[78] Zhao R, Matherly LH, Goldman ID. Membrane transporters and folate homeostasis:
intestinal absorption and transport into systemic compartments and tissues. Expert Rev Mol Med. 2009. 11:e4
[79] Gregory JF. Case study: folate bioavailability. J Nutr. 2001. 131(4 Suppl): 1376S-82S. [80] Blair JA, Johnson IT, Matty AJ. Absorption of folic acid by everted segments of rat
jejunum. J Physiol. 1974. 236(3): 653–661.
[81] Gerhard GT, Duell PB. Homocysteine and atherosclerosis. Curr Opin Lipidol. 1999. 10(5):
417-28.
[82] Ueland, P. M., H. Refsum, Beresford SA, Vollset SE. The controversy over homocysteine
and cardiovascular risk. Am J Clin Nutr. 2000. 72(2): 324-32.
[83] Smithells, RW, Sheppard S, Schorah CJ. Vitamin dificiencies and neural tube defects.
Arch Dis Child. 1976. 51(12): 944-50
[84] De-Regil LM, Fernandez-Gaxiola AC, Dowswell T, Pena-Rosas JP. Effects and safety of
periconceptional folate supplementation for preventing birth defects. Cochrane Database Syst Rev. 2010. (10): CD007950.
[85] Czeizel AE, Dudas I. Prevention of the first occurrence of neural tube defects by
periconceptional vitamin supplementation. N Engl J Med. 1992. 327(26): 1832-5.
[86] Shaw GM, Jensvold, NG, Wasserman CR, Lammer EJ. Epidemiologic characteristics of
phenotypically distinct neural tube defects among 0.7 million California births, 1983-1987. Teratology. 1994. 49(2): 143-9.
131
[87] Werler, MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of
occurrent neural tube defects. AMA. 1993. 269(10): 1257-61
[88] Tchantchou F. Homocysteine metabolism and various consequences of folate deficiency. J
Alzheimers Dis. 2006. 9(4):421-7.
[89] Carreras CW, Santi DV. The catalytic mechanism and structure of thymidylate synthase.
Annu Rev Biochem. 1995. 64:721-62.
[90] Matthews RG, Ross J, Baugh CM, Cook JD, Davis L. Interactions of pig liver serine
hydroxymethyltransferase with methyltetrahydropteroylpolyglutamate inhibitors and with tetrahydropteroylpolyglutamate substrates. Biochemistry. 1982. 21(6): 1230-8.
[91] Rutsch F1, Gailus S, Miousse IR, Suormala T, Sagné C, Toliat MR, "Identification of a
putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism." Nat Genet. 2009. 41(2): 234-239.
[92] Kim J, Gherasim C, Banerjee R. Decyanation of vitamin B12 by a trafficking chaperone.
Proceedings of the National Academy of Sciences of the United States of America. 2008. 105: 14551-14554
[93] Hannibal L1, Kim J, Brasch NE, Wang S, Rosenblatt DS, Banerjee R et al. Processing
of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product. 2009. Mol Genet Metab. 2009 Aug;97(4):260-6.
[94] Stucki M1, Coelho D, Suormala T, Burda P, Fowler B, Baumgartner MR. Molecular
mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism. Hum Mol Genet 2012. 21(6):1410-8.
[95] Padovani D, Banerjee R. A rotary mechanism for coenzyme B(12) synthesis by
adenosyltransferase. Biochemistry. 2009. 48(23):5350-7.
[96] Banerjee R, Gherasim C, Padovani D. The tinker, tailor, soldier in intracellular B12
trafficking. Current opinion in chemical biology. 2009. 13: 484-491
[97] Banerjee, R. B12 trafficking in mammals: A for coenzyme escort service. ACS Chem Biol.
2006. 1(3):149-59
[98] Russell-Jones, GJ. et Alpers DH. Vitamin B12 transporters. Pharm Biotechnol. 1999.
132
[99] Nicolas, JP, Gueant JL. Absorption, distribution and excretion of vitamin B12. Ann
Gastroenterol Hepatol. 1994. 30(6): 270-276, 281; discussion 281-272.
[100] Ganesan T, Khadra MH, Wallis J, Neal DE. Vitamin B12 malabsorption following
bladder reconstruction or diversion with bowel segments. ANZ J Surg. 2002. 72(7): 479-482.
[101] Andersen CB, Madsen M, Storm T, Moestrup SK, Andersen GR. Structural basis for
receptor recognition of vitamin b (12) intrinsic factor complex. Nature. 2010. 464(7287):445-8.
[102] Nielsen MJ, Rasmussen MR, Andersen CB, Nexo E, Moestrup SK. Vitamin B12
transport from food to the body's cells--a sophisticated, multistep pathway. Nature reviews Gastroenterology & hepatology. 2012. 9: 345-354
[103] Namour F, Dobrovoljski G, Chery C, Audonnet S, Feillet F, Sperl W et al. Luminal
expression of cubilin is impaired in Imerslund-Grasbeck syndrome with compound AMN mutations in intron 3 and exon 7. Haematologica. 2011. 96(11):1715-9.
[104] Eichholzer M, Luthy J, Moser U, Stahelin HB, Gutzwiller F (2002) [Safety aspects of
folic acid for the general population]. Praxis (Bern 1994) 91:7-16.
[105] Scott JM (1992) Folate-vitamin B12 interrelationships in the central nervous system. Proc
Nutr Soc 51:219-224.
[106] Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, Marcell PD, Stabler SP, Allen RH (1995) Neuropsychiatric disorders caused by cobalamin deficiency in
the absence of anemia or macrocytosis. 1988. Nutrition 11:181; discussion 180, 182.
[107] Guilland JC, Lequeu B. Les vitamines: Du nutriment au médicament. EM internationales.
Paris. 1992. p357
[108] Hao L, Ma J, Zhu J, Stampfer MJ, Tian Y, Willett WC, Li Z. High prevalence of
hyperhomocysteinemia in Chinese adults is associated with low folate, vitamin B12, and vitamin B6 status. J Nutr 2007, 137: 407-13.
[109] Jacques PF, Kalmbach R, Bagley PJ, Russo GT, Rogers G, Wilson PW, Rosenberg IH,Selhub J. The relationship between riboflavin and plasma total homocysteine in the
Framingham Offspring cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene. J Nutr 2002, 132: 283-8.
133
[110] Moat SJ, Ashfield-Watt PA, Powers HJ, Newcombe RG, McDowell IF. Effect of
riboflavin status on the homocysteine-lowering effect of folate in relation to the MTHFR (C677T) genotype. Clin Chem 2003, 49: 295-302.
[111] Namour F, Olivier J, Abdelmouttaleb I, Adjalla C, Debard R, Salvat C, Gueant JL.Transcobalamin codon 259 polymorphism in HT-29 and Caco-2 cells and in Caucasians:
relation to transcobalamin and homocysteine concentration in blood. Blood 2001, 97: 1092-8.
[112] Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuvel LP, Rozen R. A candidate genetic risk factor
for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet 1995, 10: 111-3.
[113] Bailey LB, Gregory JF, 3rd (1999) Polymorphisms of methylenetetrahydrofolate reductase
and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr 129:919-922.
[114] Brattstrom L, Zhang Y, Hurtig M, Refsum H, Ostensson S, Fransson L, Jones K, Landgren F, Brudin L, Ueland PM (1998) A common methylenetetrahydrofolate
reductase gene mutation and longevity. Atherosclerosis 141:315-319.
[115] Van der Put NM, van der Molen EF, Kluijtmans LA, Heil SG, Trijbels JM, Eskes TK, Van Oppenraaij-Emmerzaal D, Banerjee R, Blom HJ (1997) Sequence analysis of the
coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease. QJM 90:511-517.
[116] Bosco P, Gueant-Rodriguez RM, Anello G, Spada R, Romano A, Fajardo A, Caraci F, Ferri R, Gueant JL (2006) Association of homocysteine (but not of MTHFR 677 C>T,
MTR 2756 A>G, MTRR 66 A>G and TCN2 776 C>G) with ischaemic cerebrovascular disease in Sicily. Thromb Haemost 96:154-159.
[117] Bosco P, Gueant-Rodriguez RM, Anello G, Barone C, Namour F, Caraci F, Romano A, Romano C, Gueant JL (2003) Methionine synthase (MTR) 2756 (A --> G) polymorphism,
double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. Am J Med Genet A 121A:219-224.