Homocysteine and Glaucoma

Abstract

Elevated levels of homocysteine (Hcy), a non-proteinogenic amino acid, may lead to a host of manifestations across the biological systems, particularly the nervous system. Defects in Hcy metabolism have been associated with many neurodegenerative diseases including glaucoma, i.e., the leading cause of blindness. However, the pathophysiology of elevated Hcy and its eligibility as a risk factor for glaucoma remain unclear. We aimed to provide a comprehensive review of the relationship between elevated Hcy levels and glaucoma. Through a systemic search of the PubMed and Google Scholar databases, we found that elevated Hcy might play an important role in the pathogenesis of glaucoma. Further research will be necessary to help clarify the specific contribution of elevated Hcy in the pathogenesis of glaucoma. A discovery and conceptual understanding of Hcy-associated glaucoma could be the keys to providing better therapeutic treatment, if not prophylactic treatment, for this disease.

Keywords: aqueous humor; exfoliation glaucoma; glaucoma; homocysteine; primary open-angle glaucoma.

Figure 1

Anabolism of methionine and catabolism of homocysteine. The remethylation pathway consists of both the methionine and folate cycle. It exists to anabolize methionine. During this process, a methyl group is transferred from homocysteine. Subsequently, it enters the transsulfuration pathway whereby cystathionine β-synthase (CBS) catabolizes it into cystathionine that will eventually be catabolized into a waste product. Homocysteine is metabolized to methionine by remethylation and cystathionine by transsulfuration. Gray lettering represents coenzymes. BHMT—betaine-homocysteine S-methyltransferase, DMG—dimethylglycine, MAT—methionine adenosyltransferase, SAM—S-adenosylmethionine, SAH—S-adenosylhomocysteine, SAHH—S-adenosylhomocysteine hydrolase, MS—methionine synthase, THF—tetrahydrofolate, SHMT—serine hydroxymethyltransferase, CH₂THF—methylene tetrahydrofolate, CH₃THF—methyl tetrahydrofolate, CBS—cystathionine β-synthase, CγL—cystathionine γ-lyase. Figure 1 is sourced from [26].

Figure 2

Cobalamin synthesis. Red labels indicate enzymes in the cobalamin-synthesis pathway. Cobalamin is transported out of the lysosome and, through a series of reactions in the remethylation pathway, it is modified into methylcobalamin (active vitamin B₁₂). Blue lettering represents methyl groups while bold lettering represents proteins. ABCD4—ATP-binding cassette subfamily D member 4, Ado—adenosine, AdoHcy—adenosylhomocysteine, AdoMet—S-adenosylmethionine, AHCY—adenosylhomocysteinase, ATP—adenosine triphosphate, Cbl—cobalamin (no upper axial ligand attached), CH⁺-THF—5,10-methenyltetrahydrofolate, CH₂-THF—5,10-methylenetetrahydrofolate, CH₃-THF—5-methyltetrahydrofolate, CHO-THF—10-formyltetrahydrofolate, CHOO⁻—formate, dTMP—deoxythymidine monophosphate, Cyto—cytosol, LMBD1—lipocalin-1-interacting membrane receptor domain-containing 1, Lyso—lysosome, MATs—methionine adenosyltransferase(s), MeCbl—methylcobalamin, MMACHC—methylmalonic aciduria cblC type (with homocystinuria), MMADHC—methylmalonic aciduria cblD type (with homocystinuria), MS—methionine synthase, MSR—methionine synthase reductase, MTHFD1—methylenetetrahydrofolate dehydrogenase 1, MTHFR—dmethylenetetrahydrofolate reductase, MTs—methyltransferase(s), R-Cbl—upper axial ligand (eg, cyano-, hydroxo-) attached to cobalamin, SHMT—serine hydroxymethyltransferase. Figure 2 is sourced from [32].

Figure 3

Methylcobalamin-induced mild hyperhomocysteinemia (HHcy). A methylcobalamin (Vitamin B12) deficiency leads to HHcy from the methylation cycle and a methylTHF surplus from the folate cycle. This surplus of methyl THF leads to the accumulation of SAM due to the inhibition of glycine N-methyltransferase (GMNT). Although HHcy can stem from a deficiency in methylcobalamin, the excess methylTHF formed from that deficiency counteracts HHcy via SAM accumulation, thereby causing HHcy to be mild. THF—tetrahydrofolate, SAM—S-adenosyl methionine, SAH—S-adenosyl homocysteine, MS—methionine synthase, MTF—methyltransferase, MTHFR—methylene-THF reductase. Figure 3 is sourced from [34].

Figure 4

Eye structure. The cornea is continuous with the sclera that circumvents the eye. The sclera protects the eye while the cornea refracts light onto the lens. During that process, light traverses the iris and eventually the ciliary body to ultimately refract onto the retina. Source: Anatomy of the eye, courtesy of Amboss.

Figure 5

Trabecular and uveoscleral outflow. Thickened light blue arrows represent aqueous flow while thinned black arrows are associated with ocular structures. The thickened light blue arrows extend from the anterior chamber and into the trabecular meshwork. This directionality marks the conventional (trabecular) outflow of the aqueous humor. Though arrows are not drawn to represent the unconventional (uveoscleral) outflow, aqueous humor can also exit from the chamber angle and directly into the sclera to ultimately enter the episcleral veins. Source: Anterior chamber angle, courtesy of Amboss.

Figure 6

Cell types within the retina. Once light hits the retina, it is processed by the photoreceptors that pass information to the ganglion cells to which bipolar, horizontal, amacrine, and Müllerian glial cells contribute. The retinal pigment epithelium (RPE) maintains this processing. Source: Layers of the retina, courtesy of Amboss.