Tetrahydrobioterin (BH4) Pathway: From Metabolism to Neuropsychiatry

Abstract

: Tetrahydrobipterin (BH4) is a pivotal enzymatic cofactor required for the synthesis of serotonin, dopamine and nitric oxide. BH4 is essential for numerous physiological processes at periphery and central level, such as vascularization, inflammation, glucose homeostasis, regulation of oxidative stress and neurotransmission. BH4 de novo synthesis involves the sequential activation of three enzymes, the major controlling point being GTP cyclohydrolase I (GCH1). Complementary salvage and recycling pathways ensure that BH4 levels are tightly kept within a physiological range in the body. Even if the way of transport of BH4 and its ability to enter the brain after peripheral administration is still controversial, data showed increased levels in the brain after BH4 treatment. Available evidence shows that GCH1 expression and BH4 synthesis are stimulated by immunological factors, notably pro-inflammatory cytokines. Once produced, BH4 can act as antiinflammatory molecule and scavenger of free radicals protecting against oxidative stress. At the same time, BH4 is prone to autoxidation, leading to release of superoxide radicals contributing to inflammatory processes, and to production of BH2, an inactive form of BH4, reducing its bioavailability. Alterations in BH4 levels have been documented in many pathological situations, including Alzheimer's disease, Parkinson's disease and depression, in which increased oxidative stress, inflammation and alterations in monoaminergic function are described. This review aims at providing an update of the knowledge about metabolism and role of BH4 in brain function, from preclinical to clinical studies, addressing some therapeutic implications.

Ferroptosis: A Critical Moderator in the Life Cycle of Immune Cells

“…The GTP cyclohydrolase-1 (GCH1)-Tetrahydrobiopterin (BH4) pathway has been identified as another pathway that regulates ferroptosis. BH4 is an essential cofactor and plays multiple roles in the regulation of oxidative stress and inflammation ( 22 ). It can exert an anti-inflammatory effect by scavenging free radicals, but it is prone to auto-oxidation in the presence of molecular oxygen and therefore contributing to inflammatory processes ( 23 ) GCH1 is the first rate-limiting enzyme for BH4 biosynthesis.…”

Blockade of GCH1/BH4 Axis Activates Ferritinophagy to Mitigate the Resistance of Colorectal Cancer to Erastin-Induced Ferroptosis

“…GTP cyclohydrolase-1/tetrahydrobiopterin (GCH1/BH4) prevents cells from lipid peroxidation damage during ferroptosis induction; it is parallel to the GPX4 redox system ( Kraft et al, 2020 ; Soula et al, 2020 ). BH4 is an essential cofactor and plays multiple roles in many physiological and pathological processes, including the regulation of oxidative stress and inflammation ( Fanet et al, 2021 ). GCH1 is a critical enzyme for BH4 biosynthesis ( Harada et al, 1993 ; Thöny et al, 2000 ).…”

The Utility of Genomic Testing for Hyperphenylalaninemia

“…Following cellular exogenous uptake through specific transporters, Phe is converted in L-Tyr by PAH, an enzyme mainly expressed in the liver and kidney, which represents the rate-limiting step in Phe catabolism [15][16][17]. This conversion is dependent on tetrahydrobiopterin (BH4), as a cofactor, molecular oxygen and iron [18]. When PAH is nonfunctional, Phe accumulates in the body and is converted by different enzymes into phenylpyruvic acid, a substance that is normally produced only in small quantities.…”