The regulation of vascular tetrahydrobiopterin bioavailability

Abstract

6R l-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for several enzymes including phenylalanine hydroxylase and the nitric oxide synthases (NOS). Oral supplementation of BH4 has been successfully employed to treat subsets of patients with hyperphenylalaninaemia. More recently, research efforts have focussed on understanding whether BH4 supplementation may also be efficacious in cardiovascular disorders that are underpinned by reduced nitric oxide bioavailability. Whilst numerous preclinical and clinical studies have demonstrated a positive association between enhanced BH4 and vascular function, the efficacy of orally administered BH4 in human cardiovascular disease remains unclear. Furthermore, interventions that limit BH4 bioavailability may provide benefit in diseases where nitric oxide over production contributes to pathology. This review describes the pathways involved in BH4 bio-regulation and discusses other endogenous mechanisms that could be harnessed therapeutically to manipulate vascular BH4 levels.

Investigating the interaction between GTP-cyclohydrolase1 and its feedback regulatory protein

“…However, it should be highlighted that chronically limiting BH4 production by inhibiting the enzymes involved in the BH4 biosynthetic pathway can have detrimental downstream effects on both NO and aromatic amino acid metabolism, as BH4 is essential in maintaining both NO and aromatic amino acid homeostasis (Starr et al, 2013 BH4 is generated in the body by a de novo pathway and is recycled by the regeneration/recycling pathways. De novo synthesis and the regeneration pathways are depicted above in Figure 1.3.1.…”

“…L-phe is the only characterized small molecule that has been shown to allosterically stimulate GTPCH1 activity directly (Harada et al, 1993). Some pharmacological agents have been shown to enhance GTPCH1 expression and as a consequence can increase BH4 production in vivo such as reserpine and statins (Starr et al, 2013) (Werner-Felmayer et al, 1996). More recently, studies have focused on identifying agents that can modulate the GTPCH1-GFRP interaction and as a consequence enhance GTPCH1 activity (Li et al, 2011).…”

“…Modulating the GTPCH1-GFRP protein-protein interactions may represent a novel therapeutic target to alter BH4 bioavailability for a number of diseases (Starr et al, 2013). In order to identify compounds which can influence these interactions, we aimed to develop a high throughput screening assay, using recombinant human GTPCH1 and GFRP proteins.…”

“…Though effective as an acute intervention, chronically limiting BH4 production by GTPCH1 inhibition can have detrimental effects on both NO and aromatic amino acid metabolism (Starr et al, 2013 ).…”

“…Direct administration of BH4 at the level of the vasculature has been shown to improve endothelial dysfunction in patients with, diabetes (Heitzer et al, 2000), hypertension (Higashi et al, 2002) (Porkert et al, 2008), coronary artery disease (Maier et al, 2000), and hypercholesterolemia (Cosentino et al, 2008). Whilst these studies all demonstrated the acute efficacy of intra-arterial BH4, further trials using orally administered BH4 were less successful, an outcome attributed to oxidative inactivation of BH4 (Cunnington et al, 2012) reviewed in (Starr et al, 2013). Nevertheless, it is accepted that raising BH4 at the level of the endothelium will exert beneficial effects through raising NO bioavailability and/or reducing oxidative stress (Crabtree et al, 2011a) (Moens et al, 2007).…”