Homocysteine

Homocysteine

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Homocysteine is a non-protein amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 with the formula HSCH2CH2CH(NH2)CO2H. It is a homologue
Homologous series
In chemistry, a homologous series is a series of compounds with a similar general formula, possessing similar chemical properties due to the presence of the same functional group, and showing a gradation in physical properties as a result of increase in molecular size and mass...

 of the amino acid cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

, differing by an additional methylene (-CH2-) group. It is biosynthesized from methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...

 by the removal of its terminal Cε methyl group. Homocysteine can be recycled into methionine or converted into cysteine with the aid of B-vitamins.

While detection of high levels of homocysteine has been linked to cardiovascular disease, lowering homocysteine levels may not improve outcomes.

Structure


Homocysteine exists at neutral pH values as a zwitterion
Zwitterion
In chemistry, a zwitterion is a neutral molecule with a positive and a negative electrical charge at different locations within that molecule. Zwitterions are sometimes also called inner salts.-Examples:...

.

Biosynthesis and biochemical roles


Homocysteine is not obtained from the diet. Instead, it is biosynthesized from methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...

 via a multi-step process. First, methionine receives an adenosine group from ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

, a reaction catalyzed by S-adenosyl-methionine synthetase, to give S-adenosyl methionine
S-Adenosyl methionine
S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate and methionine by methionine adenosyltransferase . Transmethylation, transsulfuration, and aminopropylation are the...

 (SAM). SAM then transfers the methyl group to an acceptor molecule, (i.e., norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

 as an acceptor during epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

 synthesis, DNA methyltransferase
DNA methyltransferase
In biochemistry, the DNA methyltransferase family of enzymescatalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions...

 as an intermediate acceptor in the process of DNA methylation
DNA methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring...

). The adenosine is then hydrolyzed to yield L-homocysteine. L-Homocysteine has two primary fates: conversion via tetrahydrofolate (THF) back into L-methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...

 or conversion to L-cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

.

Biosynthesis of cysteine


Mammals biosynthesize the amino acid cysteine via homocysteine. Cystathionine β-synthase catalyses the condensation of homocysteine and serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...

 to give cystathionine
Cystathionine
Cystathionine is an intermediate in the synthesis of cysteine.It is generated from homocysteine and serine by cystathionine beta synthase.It is cleaved into cysteine and α-ketobutyrate by cystathionine gamma-lyase....

. This reaction uses pyridoxine
Pyridoxine
Pyridoxine is one of the compounds that can be called vitamin B6, along with pyridoxal and pyridoxamine. It differs from pyridoxamine by the substituent at the '4' position. It is often used as 'pyridoxine hydrochloride'.-Chemistry:...

 (vitamin B6) as a cofactor. Cystathionine β-lyase
Cystathionine-beta-lyase
Cystathionine-beta-lyase is an enzyme used in the biosynthesis of methionine. It is not present in humans.It is classified under ....

 then converts this double amino acid to cysteine, ammonia, and α-ketobutyrate. Bacteria and plants rely on a different pathway to produce cysteine, relying on O-acetylserine.


Methionine salvage


Homocysteine can be recycled into methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...

. This process uses N5-methyl tetrahydrofolate as the methyl donor and cobalamin (vitamin B12)-related enzymes. More detail on these enzymes can be found in the article for Methionine synthase.

Other reactions of biochemical significance


Homocysteine can cyclize to give homocysteine thiolactone, a five-membered heterocycle. Because of this "self-looping" reaction, homocysteine-containing peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

s tend to cleave themselves.

Elevated homocysteine


Deficiencies of the vitamins folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...

 (B9), pyridoxine
Vitamin B6
Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group. Several forms of the vitamin are known, but pyridoxal phosphate is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation...

 (B6), or B12
Cyanocobalamin
Cyanocobalamin is an especially common vitamer of the vitamin B12 family. It is the most famous vitamer of the family, because it is, in chemical terms, the most air-stable...

 (cobalamin) can lead to high homocysteine levels.
Supplementation with pyridoxine, folic acid, B12 or trimethylglycine
Trimethylglycine
Trimethylglycine is an organic compound that occurs in plants as either glycine betaine or a choline-containing glycine betaine compound. Trimethylglycine was the first betaine discovered by science; originally it was simply called betaine because, in the 19th century, it was discovered in sugar...

 (betaine) reduces the concentration of homocysteine in the bloodstream. Increased levels of homocysteine are linked to high concentrations of endothelial asymmetric dimethylarginine
Asymmetric dimethylarginine
Asymmetric dimethylarginine is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a conditionally-essential amino acid...

. Recent research suggests that intense, long duration exercise raises plasma homocysteine levels, perhaps by increasing the load on methionine metabolism. Chronic consumption of alcohol may also result in increased plasma levels of homocysteine.

Elevations of homocysteine also occur in the rare hereditary
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....

 disease homocystinuria
Homocystinuria
Homocystinuria, also known as cystathionine beta synthase deficiency or CBS deficiency, is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase...

 and in the methylene-tetrahydrofolate-reductase polymorphism
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...

 genetic traits. The latter is quite common (about 10% of the world population) and it is linked to an increased incidence of thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...

 and cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...

, which occurs more often in people with above minimal levels of homocysteine (about 6 μmol/L). These individuals require adequate dietary riboflavin in order for homocysteine levels to remain normal. Common levels in Western populations are 10 to 12 and levels of 20 μmol/L are found in populations with low B-vitamin intakes (e.g., New Delhi) or in the older elderly (e.g., Rotterdam, Framingham). Women have 10-15% less homocysteine during their reproductive decades than men, which may help explain the fact they suffer myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

 (heart attacks) on average 10 to 15 years later than men. However, this phenomenon is more readily explained by higher levels of estrogen, which exerts a cardioprotective effect.
|+Blood reference ranges for homocysteine:
|-
|Sex>
Age Lower limit Upper limit Unit Elevated >-
|rowspan=4| Female
12–19 years 3.3 7.2 μmol/L > 10.4 μmol/L
or
> 140 μg/dl
< 6.3 μmol/L
or
< 85 μg/dL
|-
| 45
100 >-
|rowspan=2| >60 years
4.9 11.6 >-
| 66
160 >-
|rowspan=4| Male
12–19 years 4.3 9.9 μmol/L > 11.4 μmol/L
or
> 150 μg/dL
|-
| 60
130 >-
|rowspan=2| >60 years
5.9 15.3 >-
| 80
210

Cardiovascular risks and related medical studies


A high level of blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....

 serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 homocysteine "Homocystinemia" is a powerful risk factor for cardiovascular disease. However, one study which attempted to decrease the risk by lowering homocysteine was not fruitful. This study was conducted on nearly 5000 Norwegian heart attack survivors who already had severe, late-stage heart disease. No study has yet been conducted in a preventive capacity on subjects who are in a relatively good state of health. However, Dr. Kilmer McCully has shown in several research studies that the development of arteriosclerosis requires elevated levels of homocysteine in the blood.

Studies reported in 2006 have shown that giving vitamins [folic acid, B6 and B12] to reduce homocysteine levels may not quickly offer benefit, however a significant 25% reduction in stroke was found in the HOPE-2 study
even in patients mostly with existing serious arterial decline although the overall death rate was not significantly changed by the intervention in the trial. Clearly, reducing homocysteine does not quickly repair existing structural damage of the artery architecture. However, the science is strongly supporting the biochemistry that homocysteine degrades and inhibits the formation of the three main structural components of the artery, collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...

, elastin
Elastin
Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...

 and the proteoglycans. Homocysteine permanently degrades cysteine disulfide bridges and lysine amino acid residues in proteins, gradually affecting function and structure. Simply put, homocysteine is a 'corrosive' of long-living proteins, i.e., collagen or elastin, or life-long proteins, i.e., fibrillin
Fibrillin
Fibrillin is a glycoprotein, which is essential for the formation of elastic fibers found in connective tissue.Fibrillin is secreted into the extracellular matrix by fibroblasts and becomes incorporated into the insoluble microfibrils, which appear to provide a scaffoldfor deposition of elastin.It...

. These long-term effects are difficult to establish in clinical trials focusing on groups with existing artery decline. The main role of reducing homocysteine is possibly in 'prevention' but studies in patients with pre-existing conditions found no significant benefit nor damage.

Hypotheses have been offered to address the failure of homocysteine-lowering therapies to reduce cardiovascular event frequency. One suggestion is that folic acid may directly cause an increased build-up of arterial plaque, independent of its homocysteine-lowering effects. Alternatively, folic acid and vitamin B12 may cause an overall change in gene methylation levels in vascular cells, which may also promote plaque growth. Finally, altering methlyation activity in cells might increase methylation of l-arginine to asymmetric dimethylarginine which can increase the risk of vascular disease. Thus alternative homocysteine-lowering therapies may yet be developed which show greater effects on development and progression of cardiovascular disease.

The VITATOPS trial (results presented in May 2010 by the lead investigator, Dr Graeme J Hankey of Royal Perth Hospital, Australia at the European Stroke Conference 2010, in Barcelona, Spain) has concluded that B-vitamin supplements, within 2 years, do not seem to significantly reduce subsequent stroke, MI, or vascular death in patients with a history of recent stroke and ischemic attack, despite lowering of homocysteine levels.

Alzheimer's disease and homocysteine


Studies demonstrate the connection between elevated levels of homocysteine (hyperhomocysteinaemia) and occurrence of Alzheimer's disease (AD) besides other cognitive impairments. Researchers suggest that B-group-vitamin supplementation (including folate) may possibly decrease chances to develop AD.

Bone weakness and breaks


Elevated levels of homocysteine have been linked to increased fractures in elderly persons. The high level of homocysteine will auto-oxidize and react with reactive oxygen intermediates and damage endothelial cells and has a higher risk to form a thrombus. Homocysteine does not affect bone density. Instead, it appears that homocysteine affects collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...

 by interfering with the cross-linking between the collagen fibers and the tissues they reinforce. Whereas the HOPE-2 trial showed a reduction in stroke incidence, in those with stroke there is a high rate of hip fractures in the affected side. A trial with 2 homocysteine-lowering vitamins (folate and B12) in people with prior stroke, there was an 80% reduction in fractures, mainly hip, after 2 years. Interestingly, also here, bone density (and the number of falls) were identical in the vitamin and the placebo groups.

Vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...

 supplements counter the deleterious effects of homocysteine on collagen. As they inefficiently absorb B12 from food, elderly persons may benefit from taking higher doses orally such as 100 mcg/day (found in some multivitamins) or by intramuscular injection
Intramuscular injection
Intramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of several alternative methods for the administration of medications . It is used for particular forms of medication that are administered in small amounts...

.

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