Tetrahydrobiopterin (BH4) in chronic disease
Tetrahydrobiopterin (BH4) is a tightly regulated cellular metabolite that affects a variety of neuronal and inflammatory cell functions. BH4 is produced by three enzymatic pathways, the de novo synthesis pathway, the salvage pathway and a recycling pathway. At steady state, cellular BH4 homeostasis is primarily regulated through the salvage and recycling pathways.
De novo BH4 production is significantly increased in injured peripheral nerve, as well as stimulated immune cells, including T cells, macrophages and dendritic cells. As BH4 is a cofactor for the aromatic amino acid hydroxylases, nitric oxide synthases and alkylglycerol monooxygenase, increased levels of BH4 have a pluripotent effect on pain and inflammatory mechanisms, including the excitation of neurons involved in pain signaling.
Multiple human genetic studies have linked a haplotype in the gene encoding GTP cyclohydrolase I, a BH4 synthetic enzyme, to a reduced risk of developing chronic pain after nerve injury or chronic disease.
Carriers of this haplotype have decreased upregulation of BH4 synthesis in response to injury leading to better clinical outcomes in chronic pain settings. Importantly, homozygous carriers have normal baseline levels of BH4, no deficits in normal pain sensation, and none of the clinical symptoms associated with the congenital deletion mutations in the BH4 synthesis pathway genes.
Recent studies have also demonstrated that sulfasalazine and other structurally-related sulfa drugs are potent inhibitors of sepiapterin reductase (SPR), the final enzyme in the de novo synthesis pathway. Sulfasalazine has been used clinically for over 60 years to treat autoimmune indications, such as ulcerative colitis and rheumatoid arthritis, despite a lack of understanding of the drug’s molecular mechanism of action. The possible link of the clinical activity of this approved drug to its modulation of BH4 biosynthesis provides an additional tie to human disease biology.
Safely restoring BH4 levels back to baseline by targeting one of the key BH4 synthetic enzymes has been shown to reduce inflammation and pain hypersensitivity in preclinical models. Quartet has advanced its drug discovery efforts and is developing small molecule therapies that can safely mimic the human genetic observations with pharmacological intervention.