The homocysteine network
Homocysteine is a non-protein amino acid normally found in plasma at a concentration of around 8-12 microM. The nature of plasma homocysteine is complex: only 1-2% is found as free reduced homocysteine. About 20% occurs as free oxidized forms, mainly the mixed disulfide, cysteinyl-homocysteine, but also as homocystine. The remaining 75-80%, is bound to proteins; most of this is bound to plasmaalbumin. Homocysteine has been implicated as a risk factor for a number of important diseases: high homocysteine (hyperhomocysteinemia) has been recognized as an independent risk factor for the development of vascular diseases. Previous results also showed a relationship between elevated homocysteine and neurodegenerative diseases, particularly with Alzheimer’s disease. Relatively small plasma changes may have pathological outcomes: an elevation of as little as 5 microM has been calculated to increase the risk of coronary heart disease by up to 60% in men and 80% in women.
Homocysteine metabolism is highly dependent on vitamin-derived cofactors. Methionine synthase (MtS) contains cobalamin as a prosthetic group and derives its methyl group from folic acid, a pool of one carbon. Both trans-sulfur enzymes (CBS and CGL) contain vitamin B6 as a prosthetic group. Deficiencies in any of these vitamins (vitamin B12, folic acid, and vitamin B6) are associated with hyperhomocysteinemia. Most early work on the causes focused on reduced homocysteine removal, caused by nutritional or genetic factors or by kidney disease. Folic acid deficiency is probably the most common cause of the problem. Genetic mutations have long been known to cause hyperhomocysteinemia. In particular, deficiencies of CBS or of methylene-tetrahydrofolate reductase (MTHFR) can cause homocysteinuria and very severe hyperhomocysteinemia. These are very rare inborn errors of metabolism.
How metabolism controls homocysteine?
Recently, attention has focused on the role of some genetic polymorphisms which have a wide distribution in the general population. In particular, a very common MTHFR polymorphism (C677T) is homozygous in approximately 10-16% of many populations. The replacement of valine, at position 222, with alanine produces an MTHFR that has a greater ability to dissociate and lose its FAD cofactor. This loss of activity is particularly pronounced at low concentrations of methylene-tetrahydrofolate (5-MeTHF). There is, therefore, an interesting relationship between this MTHFR polymorphism and the state of folic acid. Individuals with the C677T polymorphism have higher tHcy when plasma folate levels are low. Among other things, the ingestion of pure methionine in animals and humans raises the levels of homocysteine in the blood. This situation is characterized by a high rate of methionine catabolism, requiring an increase in flow through the raboccus enzyme, glycine N-methyltransferase, at rates greater than that homocysteine can be removed by trans-sulfur and remethylation. .
Almost 20 years ago the concept was advanced that high-flux methylation of numerous substrates, both physiological and pharmacological, plays a crucial role in determining the plasma homocysteine level. Put simply, it could often be the fault of what you eat or the drugs you take if you find yourself with high homocysteine. For example, Parkinson’s disease patients have been shown to have consistently 50% higher blood homocysteine levels when placed on L-DOPA regimens. This drug is a substrate for catechol-O-methyltransferase (COMT), the enzyme that catalyzes SAM-dependent methylation of its aromatic ring. During L-DOPA therapy, costly methylation by COMTs occurs, both centrally and peripherally. This “wasteful” metabolism of L-DOPA through methylation means that rather large doses (several grams) must be administered for the drug to take effect. The methylation of L-DOPA by COMT thus becomes responsible for the high concentrations of homocysteine.
How to reduce homocysteine levels: beyond the boring folates
Generally after medical consultation, it is customary to receive a therapy based on high doses of folic acid. While this may initially increase the availability of body folate and buffer the problem, in the long run it is realized that by discontinuing the vitamin after a few days the blood homocysteine begins to rise. Given the above, the best correction strategy should be to provide a methyl donor compound at the same time, since the toxicity of homocysteine is lost if it is re-methylated to methionine. It has been shown in rats that administering creatine and phosphatidylcholine (soy lecithin) can reduce homocysteine in the blood by 30%. Chemically, creatine is methyl-guanidinacetate; its synthesis in the liver and kidney consumes many methyl groups of SAM and can raise homocysteine levels, especially if not enough of it is introduced from the diet (meat and derivatives).
Lecithin in the liver is synthesized from phosphatidyl-EN and this requires as many as three methyl groups; therefore its synthesis is even more “expensive” than that of creatine. But there may be other hidden nutritional deficiencies as the cause of the problem. Vitamin B12 deficiency is one of them, but generally its body supplies do not compromise enough to cause the problem. Furthermore, the lack of vit. B12 causes more problems with nerve cells, and it is reported that therapeutic attempts to correct hyperhomocysteinemia with this vitamin often have not yielded results. On the other hand, it is easier for a deficiency of vitamin B6 to develop, which is the cofactor of the enzymes of the trans-sulfuration pathway (CBS and CGL) for the recovery of methionine. This is more likely to happen with a diet rich in over-processed foods and very low in fresh vegetables or fruits, which are good sources of this vitamin.
But does taking folate-based supplements help reduce cardiovascular risk in those with high homocysteine? This depends on what is causing the problem. If the subject has genetic homocystinuria, randomized control studies have been controversial in showing the reduction of cardiovascular risk with folic acid supplementation. In homocystinuria patients with severe hyperhomocysteinemia, homocysteine-lowering treatments with vitamin B6, folic acid, and hydroxycobalamin reduced cardiovascular risk. In patients who have hyperhomocysteinemia without homocystinuria, the treatment remains controversial. Randomized control studies have not been able to show a reduction in cardiovascular risk for those who lower homocysteine levels using folate therapies. But supplementing with the B complex without focusing on folic acid or vitamin B12 appears to be of greater benefit.
If one wish to insist on folic acid intake, it would be advisable to take activated forms (5-methyl-folic, methylene-tetrahydrofolate) and not the simple folic acid. Obviously, since the problem is the availability of methyl groups, it is recommended to eat foods that contain nutrients such as choline, betaine and sarcosine, which are methyl-donors. Foods rich in choline are eggs, salmon and soy, while betaine is abundant in beets, spinach, broccoli and cereals such as oats, quinoa and rye. Finally, sarcosine is abundant in legumes, turkey meat and egg yolks. Supplements based on these compounds are widely available commercially; and you can talk to your doctor or specialist about the dietary variations to follow and about a possible dietary supplement that goes beyond the usual folate.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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