Nitric Oxide Inhibits Methionine Synthase Activity in Vivo and Disrupts Carbon Flow through the Folate Pathway

Danishpajooh, Idrees O.; Gudi, Tanima; Chen, Yongchang; Kharitonov, V. G.; Sharma, Vandna; Boss, Gerry R.

doi:10.1074/jbc.m104043200

Cited by 93 publications

(102 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This conclusion is corroborated by a recent report suggesting that NO inhibits the MS reaction, thereby blocking the flow of one carbon units through the folate pathway. 4 Our results and this report prompted us to examine the possibility that NO induction of NTD is caused by inhibition of the MS reaction. To this end, eight somite stage embryos were treated with 2 mM SNAP in the presence or absence of FA.…”

Section: Dear Editormentioning

confidence: 88%

“…Nitric oxide (NO) had been shown to be able to induce NTD in 10.5-day rat embryos, 3 and biochemical studies showed that NO inhibits methionine synthase (MS), by interfering with the transfer of the methyl group from the methyl donor 5-methyl-tetrahydrofolate (5mTHF) to homocysteine. 4 We have shown that endogenously produced NO in the neuroepithelium, at the time of NT closure, plays a role in cell cycle progression 5 and the regulation of cell numbers in the developing NT. 6 We also found that high NO levels increase the demand for folates.…”

Section: Dear Editormentioning

confidence: 99%

“…The observations described here shed light on the molecular mechanisms that underlie FA deficiency and human congenital NT defects, and could give at least one molecular explanation for the necessity of FA dietary supplementation during pregnancy, and how this can prevent these devastating human congenital defects. methyl-THF (57 mCi/mmol, Amersham Biosciences) the last 4 h of the incubation period, to assess the methyl transfer through the MS reaction into TCA-precipitated material, as previously described (4). NT closure was visualized in whole mount preparations as described in (a).…”

Section: Dear Editormentioning

confidence: 99%

See 2 more Smart Citations

Folic acid rescues nitric oxide-induced neural tube closure defects

et al. 2003

View full text Add to dashboard Cite

Section: Dear Editormentioning

confidence: 88%

Section: Dear Editormentioning

confidence: 99%

Section: Dear Editormentioning

confidence: 99%

See 1 more Smart Citation

Folic acid rescues nitric oxide-induced neural tube closure defects

et al. 2003

View full text Add to dashboard Cite

“…The present studies demonstrated an ethanol-induced inhibition of MS activity that could explain the reduced liver methionine and SAM levels (Tables 1 and 2). Others showed that nitric oxide inactivates MS (60) because of interaction with its cobalamin cofactor (61). MAT activity is reduced posttranslationally through nitrosylation of cysteine residue 121 in MATI͞III (62), whereas its activity is maintained in part by GSH (63).…”

Section: Discussionmentioning

confidence: 99%

Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig

Halsted

Villanueva

Devlin

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

183

179

View full text Add to dashboard Cite

Alcoholic liver disease is associated with abnormal hepatic methionine metabolism and folate deficiency. Because folate is integral to the methionine cycle, its deficiency could promote alcoholic liver disease by enhancing ethanol-induced perturbations of hepatic methionine metabolism and DNA damage. We grouped 24 juvenile micropigs to receive folate-sufficient (FS) or folate-depleted (FD) diets or the same diets containing 40% of energy as ethanol (FSE and FDE) for 14 wk, and the significance of differences among the groups was determined by ANOVA. Plasma homocysteine levels were increased in all experimental groups from 6 wk onward and were greatest in FDE. Ethanol feeding reduced liver methionine synthase activity, S-adenosylmethionine (SAM), and glutathione, and elevated plasma malondialdehyde (MDA) and alanine transaminase. Folate deficiency decreased liver folate levels and increased global DNA hypomethylation. Ethanol feeding and folate deficiency acted together to decrease the liver SAM͞S-adenosylhomocysteine (SAH) ratio and to increase liver SAH, DNA strand breaks, urinary 8-oxo-2 -deoxyguanosine [oxo(8)dG]͞mg of creatinine, plasma homocysteine, and aspartate transaminase by more than 8-fold. Liver SAM correlated positively with glutathione, which correlated negatively with plasma MDA and urinary oxo(8)dG. Liver SAM͞SAH correlated negatively with DNA strand breaks, which correlated with urinary oxo(8)dG. Livers from ethanol-fed animals showed increased centrilobular CYP2E1 and protein adducts with acetaldehyde and MDA. Steatohepatitis occurred in five of six pigs in FDE but not in the other groups. In summary, folate deficiency enhances perturbations in hepatic methionine metabolism and DNA damage while promoting alcoholic liver injury. F olate deficiency is among the most common nutritional abnormalities in chronic alcoholic patients, especially in those who have developed alcoholic liver injury (1-5). In addition to poor diet, folate deficiency in chronic alcoholism can be ascribed to decreased intestinal absorption and hepatic uptake, increased renal excretion, and increased oxidative cleavage of the folate molecule (6-12). Folate in its 5-methyltetrahydrofolate (5-MTHF) form is integral to methionine metabolism. Folate deficiency perturbs hepatic methionine metabolism (13,14), which is associated with DNA nucleotide imbalance and increased hepatocellular apoptosis in experimental animals fed folate-deficient (FD) diets or exposed to chronic ethanol (15,16).Hepatic methionine metabolism is regulated by the availability of dietary and endogenous folate that appears in the circulation as 5-MTHF and is the substrate with cofactor vitamin B 12 for the methionine synthase (MS) reaction that generates methionine from homocysteine (Hcy) (see supporting information, which is published on the PNAS web site, www.pnas.org). In the alternate salvage pathway for methionine synthesis, choline is the precursor of betaine, which is the substrate for betaine homocysteine methyltransferase (BHMT). The methionine adeno...

show abstract

“…In addition, direct loss of vitamins and mineral trace elements from the organism of the animals can occur during exposure to an external stress (such as for example, a climatic stress), since MS-Co(II), an inactivated form of vitamin B12 produced by oxidation of MS-Co(I) in the course of enzymatic methionine synthesis, can be oxidized by ROS [110,115]. Indeed, inactivation of vitamin B12 by • NO [115] has been reported and is involved in pernicious anemia in humans, after disturbing both methionine synthesis and carbon flow through the folate pathway [116].…”

Section: Defense Against Ros and The Outcome Of Gestationmentioning

confidence: 99%

Gestation linked radical oxygen species fluxes and vitamins and trace mineral deficiencies in the ruminant

2006

View full text Add to dashboard Cite

-In mammals, radical oxygen species (ROS) are essential factors of cell replication, differentiation and growth (oxidative signal), notably during gestation, but are also potentially damaging agents. In Women, ROS play a role in remodeling of uterine tissues, implantation of the embryo, settlement of the villi and development of blood vessels characteristic of gestation. The body stores of vitamins and minerals of gestating females are used to keep ROS fluxes at a level corresponding to oxidative signals and to prevent an imbalance between their production and scavenging (oxidative stress), which would be detrimental to the mother and fetus. There is some evidence that, although based on different regulatory mechanisms, most of the effects of ROS reported in humans also occur in pregnant ruminant females, some of which have been actually reported. Many vitamins and trace elements have dual effects in the organism of mammals: (a) they are involved in the control of metabolic pathways or/and gene expression, (b) but most of the time they also display ROS trapping activity or their deficiencies induce high rates of ROS production. Deficiencies induce different disorders of gestation and can be induced by different kinds of stress. An example is given, corresponding to the decreased contents of cobalt of forages, when exposed to sustained heavy rains, so that the supply of vitamins B12 to the organism of the ruminant that grazes them is reduced and failure of gestation is induced. Outdoor exposure of ruminants to adverse climatic conditions by itself can increase the vitamin and trace element requirements. Adaptation of production systems taking into account these interactions between gestation and sources of stress or change of the quality of feeding stuffs as well as further developments of knowledge in that field is necessary to promote sustainable agricultural practices.gestation / ovine / bovine / vitamins / trace elements / antioxidant enzymes / radical oxygen species / radical phenomena

show abstract

Nitric Oxide Inhibits Methionine Synthase Activity in Vivo and Disrupts Carbon Flow through the Folate Pathway

Cited by 93 publications

References 39 publications

Folic acid rescues nitric oxide-induced neural tube closure defects

Folic acid rescues nitric oxide-induced neural tube closure defects

Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig

Gestation linked radical oxygen species fluxes and vitamins and trace mineral deficiencies in the ruminant

Contact Info

Product

Resources

About