Homocysteine and methionine

BIOCHEMISTRY

1. HOMOCYSTEINE & methionine effects on cardiovascular diseases JELILAT KAREEM KUZIVA ZVAREVASHE EMILY CLARKE

2. METHIONINE The major nonprotein fate of methionine is conversion to S - adenosylmethionine , the principal source of methyl groups in the body . Loss of the methyl and adenosyl group yields homocytseine which is eventually processed to α- ketobutyrate . This keto acid is then decarboxylated to propionyl CoA which is finally processed to succinyl CoA.

3. HOMOCYSTEINE Hcys is a non-protein α-amino acid and is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-).

4. It is a metabolic byproduct of protein metabolism and in particular the metabolism of methionine. It is metabolized through two pathways: remethylation and transsulfuration .   Remethylation requires folate and   B12  coenzymes while transsulfuration requires pyridoxal-5-phosphate, the B6 coenzyme.

5. The Methylation Cycle and Hcys : Typically , about 50% of Hcys is remethylated and the remaining Hcys is transsulfurated to cysteine. The cysteine that is formed is then used to produce glutathione. Glutathione is a powerful anti-oxidant that protects cellular components against oxidative stress. Vitamin B2 and magnesium are involved in Hcys metabolism. Without proper levels of methylated B6, B12, folate , B2 and magnesium, dangerous levels of Hcys may build up in the body.

6. HOMOCYSTEINE AND CV DISEASES

7. What causes elevated Hcys levels ? Hcys levels increase in the body when the metabolism of methionine to cysteine is impaired. This may be due to dietary deficiencies in vitamin B6, vitamin B12, and folic acid . While alcoholics tend to be malnourished and lacking in B vitamins, alcohol itself may independently cause Hcys levels in the blood to rise . Can elevated Hcys levels be hereditary ? Genetic abnormalities may affect the body's ability to metabolize Hcys to cysteine , causing elevation of Hcys levels in the blood and urine .

8. HYPERHOMOCYSTEINEMIA HyperHcys-emia is defined as a medical condition characterized by an abnormally high level (above 15  μmol /L) of Hcys in the blood. There are two types of hyperhomocysteinemia : ( 1 ) the rare but severe forms are due to major genetic mutations of the enzymes implicated in Hcys metabolism ; The enzymes involved can be methylene tetrahydrofolate reductase , methionine synthase, and cystathionine - β- synthase. The most common one is single nucleotide polymorphisms of 5,10-methylene tetrahydrofolate reductase which has been associated with mild and moderate hyperhomocysteinemia .

9. ( 2) the more common forms cause moderately elevated Hcys levels related to a pathogenesis such as genetic and environmental factors. EFFECTS OF HYPERHOMOCYSTEINEMIA ON CV DISEASES There has been an indication towards a significant correlation between hyperhomocysteinemia and cardiovascular disease and its complications such as heart attacks and strokes. It is also believed that hyperhomocysteinemia leads to endothelial cell damage , and reduction in the flexibility of vessels .

10. High level of plasma Hcys in blood raises the size of smooth muscles, and as a result, the growing blood vessel wall becomes narrow and obstructs blood supply . Some reports suggest that increased levels of Hcys are linked to high concentrations of endothelial asymmetric dimethylarginine (ADMA).

11. Hyperhomocysteinemia has been associated with an increased risk of cardiovascular disease in end-stage renal disease, especially in patients without malnutrition and inflammation . Also, plasma ADMA levels have been associated with cardiovascular disease in renal failure patients. Both Hcys and ADMA are thought to mediate their adverse vascular effects by impairing endothelial , nitric oxide-dependent function resulting in decreased vasodilatation, increased smooth muscle cell proliferation , platelet dysfunction and increased monocyte adhesion .   Hcys -induced injury to the arterial wall is one of the factors that can initiate the process of atherosclerosis, leading to endothelial dysfunction and eventually to heart attacks and stroke.

12. It has long been known that high levels of Hcys is an independent predictor of CV disease. However , in the absence of a clear mechanism linking Hcys to CV disease, there has been an ongoing debate about whether this relationship is one of cause and effect or whether an elevated level of plasma Hcys is an epiphenomenon, reflecting the presence of some other proatherogenic factor that is actually responsible for the cardiovascular disease . The mechanistic link may be a Hcys -induced reduction in the concentration of high density lipoproteins (HDLs ). A report made it known that Hcys reduces the concentration of HDL cholesterol in plasma by inhibiting the hepatic synthesis of apoA -I, the main HDL apolipoprotein . So there is a real possibility that a Hcys -induced inhibition of apoA -I synthesis is the mechanism linking Hcys to the development of atherosclerosis.

13. Common levels of hyperhomocysteinemia in Western populations are 10- 12 μ mol /L, and a rise of about 20 μ mol /L are found in populations with low Vit . B intake (New Delhi as an instance ). Women have 10- 15% less Hcys during their reproductive years than men; this explains why they suffer myocardial infarction 10- 15 years later than men.

14. HOMOCYSTINURIA A lso called Classical homocystinuria , because it is a deficiency of cystathionine beta synthase deficiency . Children born with homocystinuria , often died at a very young age with advanced atherosclerosis in their arteries because t his defect leads to a multi-systemic disorder of the connective tissue,  muscles, (CNS ), and  CV system .  Homocystinuria represents a group of hereditary metabolic disorders characterized by an

15. accumulation of the   homocysteine in the  serum and an increased excretion of homocysteine in the  urine. Signs and symptoms of homocystinuria that may be seen include the following : A family history of homocystinuria Flush across the cheeks Musculoskeletal Tall, thin build resembling  Marfanoid habitus Long limbs ( dolichostenomelia ) High-arched feet ( pes cavus ) Knock knees (genu valgum ) Intellectual disability Seizures Psychiatric disease

16. Eye anomalies Vascular disease Extensive atheroma formation at a young age which affects many arteries but not the coronary arteries Intravascular  thrombosis Symptoms of Elevated Hcys Elevated homocysteine levels in the body DO NOT cause any symptoms Elevated Hcys levels affect the interior lining of blood vessels in the body, increasing the risk of atherosclerosis or narrowing of blood vessels. This can result in early heart attack and stroke

17. There is a relationship between the levels of Hcys in the body and the size of the carotid arteries that supply the brain with blood; the higher Hcys level, the narrower or more stenosed the carotid artery . Alzheimer's disease and other types of dementia may be more frequently seen in patients with increased Hcys in the blood In pregnancy, Hcys levels tend to decrease. Elevated Hcys levels may be associated with some fetal abnormalities and with potential blood vessel problems in the placenta, causing abruption.

18. The risk of deep vein thrombosis and  pulmonary embolism may also be linked to elevated homocysteine levels in the body . There may be a relationship between elevated homocysteine levels and broken bones, especially in the elderly.

19. TREATMENT Blood tests that show Hcys levels above 8 μ mol /L are an indication of methylation deficiencies and elevated risk of cardiovascular disease . These individuals should supplement their diet with pre-methylated forms of B vitamins such as methyl- folate , methyl-B12, Pyridoxal 5′ Phosphate, riboflavin, trimethylglycine , magnesium and choline. N-Acetyl Cysteine and  lipoic acid  are also great supplements to help boost glutathione and lower Hcys levels. High quality omega-3 fatty acids and medium chain saturated fats from coconut oil are critical players in lowering Hcys as well.

20. The effects of vitamin treatment may be monitored by routine, scheduled blood tests . However, evidence to support the value of treating elevated blood levels of homocysteine (except in cases of severely high levels) in the general population is lacking. Therefore, it is not recommended that people be treated with vitamins to lower homocysteine levels as a way to prevent vascular disease. Some patients do not respond to the vitamin supplementation and are considered pyridoxine-resistant. A diet low in methionine is recommended in addition to the B vitamins.

21. THANK you for listening !!!