**2. Homocysteine metabolism**

Homocysteine is a 4-carbon amino acid attached to a sulphydryl group. Homocysteine is involved in the transfer of methyl groups when it is synthesized from S-adenosylmethionine methylase and adenosyl-homocysteinase (please see Figure 1). Homocysteine may also be transformed back to methionine or catabolised to cystathionine. In the latter pathway, homocysteine combines with serine via cystathione beta-synthase to yield cystathionine which, via a gamma-lyase enzyme, is cleaved to yield free cysteine and a ketobutyrate. Cysteine is then metabolized via gamma-glutamyl synthase/glutathione synthase to reduced glutathione (GSH) which is important for electron storage with oxidized glutathione (GSSG), as shown in Figure 1. Homocysteine is therefore linked to two important pathways in the body one involving methylation processes and the other a transsulphuration pathway that may be of importance in redox reactions in the maintenance of homeostasis (Medina et al, 2001; Giusti et al, 2008). Figure 1 shows how closely intertwined these two pathways are.

A further role for homocysteine may arise out of its capacity to bind to transfer ribonucleic acid (tRNA) which in certain circumstances is thought to produce a highly reactive derivative, homocysteine thiolactone (Jakubowski & Goldman, 1993; Jakubowski 2000). Homocysteine is usually immediately methylated to methionine-tRNA but when this process is impaired or inadequate, the reactive species, homocysteine thiolactone, is formed (Antonia et al 1997). This form of HCY can rapidly homcysteinylate any of several enzymes causing alteration in enzyme activity thus leading to disordered homeostasis and redox imbalance (Booth et al, 1997).

In spite of the above rather interesting theory it was not known how plasma HCY enters cells to affect such change. The transporter for HCY into the endothelial cell has recently been found and shown to be sodium and lysozyme dependent (Jiang et al 2007) and this explains how HCY can enter endothelial cells and become incorporated into proteins (Jakubowski et al, 2000). It is not known whether such mechanisms exist for non-endothelial cells, in particular for alveolar epithelial cells.

2000). These results were supported by Andersson who showed that high plasma homocysteine levels were associated with low reduced glutathione levels in 2000 in the plasma of COPD patients (Andersson 2000). Thus establishing an almost inverse relation between the levels of homocysteine and reduced glutathione and giving rise to the hypothesis that homocysteine should be elevated in COPD because of impaired oxidative stress. Taken together this series of studies demonstrate that COPD, the most common

Chronic obstructive pulmonary disease is a disease mainly of the middle-aged and elderly. It results from an abnormal pro-inflammatory response of the lung to inhaled noxious stimuli that leads to an unrelenting accelerated decline in forced expiratory volume in the first second of exhalation (FEV1) and is characterised by a ratio of FEV1 to forced vital capacity (FVC) of less than 70%. The disease is currently estimated as the fourth leading cause of death world-wide and it is expected to become the third leading cause within the

In this chapter we will examine the evidence for the association of hyperhomocysteinaemia

Homocysteine is a 4-carbon amino acid attached to a sulphydryl group. Homocysteine is involved in the transfer of methyl groups when it is synthesized from S-adenosylmethionine methylase and adenosyl-homocysteinase (please see Figure 1). Homocysteine may also be transformed back to methionine or catabolised to cystathionine. In the latter pathway, homocysteine combines with serine via cystathione beta-synthase to yield cystathionine which, via a gamma-lyase enzyme, is cleaved to yield free cysteine and a ketobutyrate. Cysteine is then metabolized via gamma-glutamyl synthase/glutathione synthase to reduced glutathione (GSH) which is important for electron storage with oxidized glutathione (GSSG), as shown in Figure 1. Homocysteine is therefore linked to two important pathways in the body one involving methylation processes and the other a transsulphuration pathway that may be of importance in redox reactions in the maintenance of homeostasis (Medina et al, 2001; Giusti

A further role for homocysteine may arise out of its capacity to bind to transfer ribonucleic acid (tRNA) which in certain circumstances is thought to produce a highly reactive derivative, homocysteine thiolactone (Jakubowski & Goldman, 1993; Jakubowski 2000). Homocysteine is usually immediately methylated to methionine-tRNA but when this process is impaired or inadequate, the reactive species, homocysteine thiolactone, is formed (Antonia et al 1997). This form of HCY can rapidly homcysteinylate any of several enzymes causing alteration in enzyme activity thus leading to disordered homeostasis and redox

In spite of the above rather interesting theory it was not known how plasma HCY enters cells to affect such change. The transporter for HCY into the endothelial cell has recently been found and shown to be sodium and lysozyme dependent (Jiang et al 2007) and this explains how HCY can enter endothelial cells and become incorporated into proteins (Jakubowski et al, 2000). It is not known whether such mechanisms exist for non-endothelial

et al, 2008). Figure 1 shows how closely intertwined these two pathways are.

chronic respiratory disorder, is linked to hyperhomocysteinaemia.

next ten years (GOLD 2010).

and COPD and discuss its implications.

**2. Homocysteine metabolism** 

imbalance (Booth et al, 1997).

cells, in particular for alveolar epithelial cells.

Fig. 1. Modified from Tehlivets (2011). The Figure shows the linkage between HCY and glutathione.
