Homocysteine and folate

Apeland T, Mansoor MA, Strandjord RE, Vefring H, Kristensen O. Folate, homocysteine and methionine loading in patients on carbamazepine. Acta Neurol Scand 2001 103(5) 294-9. 

Goff DC, Bottiglieri T, Arning E, Shih V, Freudenreich O, et al. 2004. Folate, homocysteine, and negative symptoms in schizophrenia. Am J Psychiatry 161(9) 1705-1708. 

Figure 8 Extended folate metabolism, including compartmentation. MTHFR, methylenetetrahydrofolate reductase SHMT, serine hydroxymethyltransferase BHMT, betaine homocysteine methyltransferase, MAT, methionine adenosyltransferase SAH-hydrolase, S-adenosylhomocysteine hydrolase MT, methyltransferase CBS, cystathionine /i-synthase SAM, S-adenosylmethionine SAH, S-aden-osylhomocysteine THF, tetrahydrofolate and 5-MeTHF, 5-methyltetrahydrofolate. (Reproduced from Van der Put etal. (2001) Folate, homocysteine and neural tube defects An overview. Experimental Biology and Medicine 226 243-270.)...

Morris MS. Folate, homocysteine, and neurological function. Nutr CUn Care 2002 5 124-32. 

Van der Put NMJ, Van Straaten HWM, Trijbels FJM, Blom HJ. Folate, homocysteine and neural tube defects An overview. Exp Biol Med 2001 226 243-270. 

The evaluation of an optimal diagnostic threshold for active vitamin B12 was carried out by testing holoTC concentration on 250 selected serum specimens. Figure 28.3 shows weak correlation between holoTC and tBi2 levels on all specimens (r = 0.420). No correlation was found between holoTC and other metabolically correlated parameters (folate, homocysteine and creatinine). 

Supplements of 400 Ig/d of folate begun before conception result in a significant reduction in the incidence of neural mbe defects as found in spina bifida. Elevated blood homocysteine is an associated risk factor for atherosclerosis, thrombosis, and hypertension. The condition is due to impaired abihty to form methyl-tetrahydrofolate by methylene-tetrahydrofolate reductase, causing functional folate deficiency and resulting in failure to remethylate homocysteine to methionine. People with the causative abnormal variant of methylene-tetrahydrofolate reductase do not develop hyperhomocysteinemia if they have a relatively high intake of folate, but it is not yet known whether this affects the incidence of cardiovascular disease. 

In mammals and in the majority of bacteria, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, catalyzing the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate via two methyl transfer reactions. This cytoplasmic reaction is catalyzed by methionine synthase (5-methyltetrahydrofolate-homocysteine methyl-transferase), which requires methyl cobalamin (MeCbl) (253), one of the two known coenzyme forms of the complex, as its cofactor. 5 -Deoxyadenosyl cobalamin (AdoCbl) (254), the other coenzyme form of cobalamin, occurs within mitochondria. This compound is a cofactor for the enzyme methylmalonyl-CoA mutase, which is responsible for the conversion of T-methylmalonyl CoA to succinyl CoA. This reaction is involved in the metabolism of odd chain fatty acids via propionic acid, as well as amino acids isoleucine, methionine, threonine, and valine. 

Hill et al. (141) hrst observed that light-stable yellow alkylcorrinoids could be synthesized. When methylcobalamin was treated with picrate, a yellow corrinoid was isolated which was shown to be stable to light, but unstable to cyanide. Similarly, Taylor and Weissbach (67) demonstrated that the methylcorrinoid-enzyme complex of N5-methyl-tetrahydro-folate-homocysteine transmethylase was stable to light, but isolation of... 

Fig. 14.10 Folate metabolism and role of MTHFR. Genetically reduced MTHFR activity affects the distribution between folate species required for protein and DNA synthesis. Higher availabil ity of 5,10-methylenetetrahydrofolate (CH2THF) potentiates the TS inhibition by 5-FdUMP, the active metabolite of 5-FU. Hey, homocysteine Met, methionine CH3HF, 5-methyltetrahydrofolate TS, thymidylate synthase 5-FdUMP, fluorodeoxyuridine monophosphate.

Answen B. Methyhnalonyl CoA mutase requires Bj but not folate for activity. Macrocytic anemia, elevated homocysteine, and macrocytic anemia can be caused by either B,2 or folate deficiency. 

Management is essentially the same as for folate deficiency but the site of the lesion, that may necessitate further investigation and treatment, needs accurate definition by means of the Schilling test. Additional useful determinations are homocysteine and methylmalonic acid levels. 

Moat SJ, Lang D, McDowell IF, Clarke ZL, Madhavan AK, Lewis MJ, Goodfellow J (2004) Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem 15 64-79... 

The homocystinurias are a group of disorders involving defects in the metabolism of homocysteine. The diseases are inherited as autosomal recessive illnesses, characterized by high plasma and urinary levels of homocysteine and methionine and low levels of cysteine. The most common cause of homocystinuria is a defect in the enzyme cystathionine /3-synthase, which converts homocysteine to cystathionine (Figure 20.21). Individuals who are homozygous for cystathionine [3-synthase deficiency exhibit ectopia lentis (displace ment of the lens of the eye), skeletal abnormalities, premature arte rial disease, osteoporosis, and mental retardation. Patients can be responsive or non-responsive to oral administration of pyridoxine (vitamin B6)—a cofactor of cystathionine [3-synthase. Bg-responsive patients usually have a milder and later onset of clinical symptoms compared with B6-non-responsive patients. Treatment includes restriction of methionine intake and supplementation with vitamins Bg, B, and folate. 

Some antiepileptic drugs have been associated with low serum and erythrocyte folate concentrations and high total plasma homocysteine concentrations in some patients. The concentrations of folate and homocysteine have been measured in 42 patients taking carbamazepine and 42 matched healthy controls (241). Patients taking carbamazepine had significantly lower serum and erythrocyte folate concentrations. There was hyperhomocystinemia (over 15 gmol/l) in 24% of the patients and 5% of the controls. 

Hall, M Gamble, M Slavkovich, V. et al. (2007) Determinants of arsenic metabolism Blood arsenic metabolites, plasma folate, cobalamin, and homocysteine concentrations in maternal-newborn pairs. Environmental Health Perspectives, 115 (10), 1503-9. 

The difference between the outcome of the Swiss Heart Study and that of FACIT illustrates how difficult it is to explain the results in terms of the biological effects of vitamin therapy. The positive results of the Swiss Heart Study seem to confirm the classical homocysteine hypothesis, which holds that homocysteine is an important atherosclerotic determinant and that lowering of homocysteine with vitamin therapy might reduce the rates of cardiovascular events. However, it is more difficult to explain the results of FACIT by an adverse effect of low plasma homocysteine, and consequently, a less simplistic perspective on the methionine-homocysteine metabolism and the multiple effects of folate, B6, and B 2 is needed. 

How does a diet deficient in folate affect homocysteine and methionine metabolism ... 

Indirect indicators of vitamin B12 deficiency include measurements of the metabolites homocysteine and methylmalonic acid (MMA) in serum and MMA in urine (see the Biochemical Perspectives section). Whereas the serum homocysteine concentration increases during folate or vitamin B12 deficiencies, the serum and urine MMA concentrations increase only in vitamin B12 deficiency. Therefore, MMA determinations can be used to differentiate vitamin B12 deficiency from folate deficiency. The normal concentration of MMA in serum ranges from 0.08 to 0.28 pmol/L. MMA is quantified using gas-liquid chromatography and mass spectrometry. Elevated concentrations of MMA and homocysteine in serum may precede the development of hematological abnormalities and reductions in serum vitamin B12 concentrations. One should be aware that other conditions, including renal in sufficiency and inborn errors of metabolism, can also result in elevated serum levels of MMA. 

As discussed in Section 10.3.4.2, the metabolic fate of homocysteine arising from methionine is determined not only by the activity of cystathionine synthetase and cystathionase, hut also the rate at which it is remethylated to methionine (which is dependent on vitamin B12 and folate status) and the requirement for cysteine. 

Change A, Potier De Courcy G, Boisson F, Guilland JC, Barbe F, Perrin MO, Christides JP, Rabhi K, Pfister M, Galan P, Hercberg S, and Nicolas JP (2000b) 5,10-Meth-ylenetetrahydrofolate reductase common mutations, folate status and plasma homocysteine in healthy French adults of the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) cohort. British Journal of Nutrition 84, 891-6. 

Homocysteine is metabolized in the liver, kidney, small intestine and pancreas also by the transsulfuration pathway [1,3,89]. It is condensed with serine to form cystathione in an irreversible reaction catalyzed by a vitamin B6-dependent enzyme, cystathionine-synthase. Cystathione is hydrolyzed to cysteine that can be incorporated into glutathione or further metabolized to sulfate and taurine [1,3,89]. The transsulfuration pathway enzymes are pyridoxal-5-phosphate dependent [3,91]. This co-enzyme is the active form of pyridoxine. So, either folates, cobalamin, and pyridoxine are essential to keep normal homocysteine metabolism. The former two are coenzymes for the methylation pathway, the last one is coenzyme for the transsulfuration pathway [ 1,3,89,91 ]. 

A study of 2K human subjects revealed that treatment with three vitamins together (folate, vitamin and vitamin Bu) can provoke a decline of plasma homt>cysteine from an initial level of about 12 piM to the lower level of 8 xM (Naurath ei a]., 1995). A study of 100 men with moderate levels of plasma homocysteine (18-40 pM) involved separate supplements of placebo, folic acid, vitamin 15i2, or vitamin E. Folic add alone resulted in a 40% decline in plasma homocysteine. Vitamin B] alone provoked a 15% decrease in the amino acid, while vitamin... 

Is there any relationship between folate status and methionine intake Methionine has a pro-folate effect, as revealed in the Folate section. In brief, dietary methionine spares the use of 1-carbon units that might otherwise be used for the conversion of homocysteine to methionine. Furthermore, methionine is converted in the cell to SAM, which in turn inhibits 5,i0-methylenc-H4folate reductase. This inhibition prevents the useless accumulation or trapping of 1-carbon units in the form of S-methyl-H folate, and allows the folate cofactors to be used for other purposes, such as the synthesis of thymidylate. 

Vtamin A supplementation, 564-565 Vitamin B(, 493, 541-542 aminotranK/ei ase, 209 assessmenl of status, 546-550 biochcinistry, 542-545 cardiovascular disease and, 553 homocysteine and, 550-554 homocysbnuria, 550,554 toxidty, 550 water solubility, 27 Vitamin Bs deficiency, 545-546 Vitamin supplements, 551 Vitamin Bu, 493,507, 516 absorption, 81-82 assessment of status, 522-524 biocbemistry, 516-517 chemical structure, 517 Cobalt and, 4t homocystBine and, 553 Vitamin Bij dehdency, 517-524 causes of, 518-522 elderly population, 521,553 folate deficiency and, 507, 511-312, 518 hematologic signs, 513... 

A median increase in serum homocysteine of 50% (range 27-333%) was found in seven healthy male volnnteers after a 2-week course of trimethoprim 300 mg bd (59). Concomitantly, serum folate concentrations fell significantly. By day 50, baseline values of homocysteine and folate were regained. Since tetrahydrofolate serves as a methyl group carrier in the remethylation of homocysteine to methionine, the inhibitory effect of trimethoprim on dihydrofolate reductase may be most important, but other mechanisms could not be excluded. 

A study of 1401 subjects involved measuring plasma homocysteine and measuring the lesions in the carotid artery, one of the arteries in the body that tends to acquire atherosclerotic lesions. The thickness of the lesions were measured by ultrasonography. Plasma folate, vitamin Bg, and vitamin B12 were also measured. A correlation was found between narrowing of the artery and homocysteine levels at above 15 xM homocysteine. A correlation with narrowing of the artery was also found with folate levels below 2.5 ng/ml, and with vitamin Bg levels below 30 nM (Selhub et al, 1995). A study of 231 normal subjects and 304 patients with atherosclerosis (coronary artery under 30% normal diameter) revealed a striking correlation between plasma homocysteine of 12 pM, or greater, and atherosclerosis (Robinson et al, 1995). These studies help define an upper limit of acceptable plasma homocysteine levels. 

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