Enzymatic Homocysteine Background

Introduction

Vincent du Vigneaud
Homocysteine (Hcy), a sulphurcontaining amino acid, was first isolated from a urinary bladder stone in 1933 by Vincent du Vigneaud who later received the Nobel Prize in chemistry in 1955.

In 1969, Dr. Kilmer McCully, a Harvard pathologist, published a paper in the American Journal of Pathology, describing vascular pathology in patients suffering from homocystinuria, suggesting for the first time that elevated Hcy was a likely cause of premature vascular disease. Dr. McCully encountered two children with a genetic disorder called homocystinuria. In patients with this disorder, Hcy is present in the blood in excess amounts and excreted in the urine. Strikingly, these children, one of them a boy only 2 months old, had an advanced stage of arteriosclerosis that closely resembled that seen in older adults with advanced cardiovascular disease. These young patients also had extremely high levels of Hcy in their blood and urine and no lipid deposits in their vascular plaques. Autopsy tissue from an 8 year old homocystinuria child who died of a stroke looked exactly like those of elderly men with arteriosclerosis. These

Kilmer McCully
observations led Dr. McCully to hypothesize that these conditions could be the direct result of exposure to an elevated level of Hcy in the circulating blood. However, this hypothesis was not accepted by the medical community until the late 1980s when similar observations were confirmed by European doctors.

By the 1990s, an explosion of studies examining this hypothesis has brought Hcy and its role as a risk factor for cardiovascular disease into a whole new light. Today, it is widely accepted that an elevated level of Hcy (>15 μmol/L) is an independent risk factor for cardiovascular disease. Recent studies have also demonstrated a strong correlation between elevated Hcy levels and diseases such as diabetes, Alzheimer's, osteoporosis, and renal failure. More and more research data is beginning to merge into a consensus that Hcy is an important indicator for overall health status. Professor Per-Magne Ueland, a leading scientist in Hcy research from the University of Bergen/Haukeland Hospital, Norway, states: "Hcy is in fact a health measure. There is an extraordinary connection between the quantity of Hcy and the patient's general state of health. The Hcy value is an indicator for both health and non-health factors such as exercise, smoking, coffee drinking, cholesterol, vitamins, etc."

What is Hcy?

Hcy is a sulphur-containing amino acid with a molecular weight of 135.2 Dalton. Hcy is not contained in the protein or DNA, but is a metabolic intermediary derived from the essential sulphur containing amino acid, methionine.

Hcy Metabolism

Hcy is produced from S-adenosyl-L-homocysteine (SAH) by S-adenosyl-homocysteine hydrolase. SAH is a transmethylation product from S-adenosyl-methionine (SAM) that is made from methionine and ATP. In the metabolic cycle, Hcy is either remethylated to methionine through methionine synthase or degraded to cysteine through cystathionine beta-synthase. Intracellular Hcy is also released into blood and urine. Vitamin B12, folate, and B6 are needed in the Hcy remethylation pathway and transsulfuration pathway.

What is Total Hcy?

Plasma Hcy exists in different forms. The major form is the protein (mainly albumin) bound form which accounts for 70–80% of total Hcy. The other oxidized forms are mixed disulfides of Hcy-Hcy or Hcy-Cys which account for 5–10% of total Hcy. Free Hcy, or so called reduced Hcy, is less than 1% in plasma (see Table 1). Total Hcy refers to the sum of protein bound, oxidized and reduced Hcy, and is expressed as tHcy. In most clinical laboratories, tHcy testing is performed.