Pathway: Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation

Reactions in pathway: Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation :

Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation

Tetrahydrobiopterin (BH4) is an essential co-factor for the aromatic amino acid hydroxylases and glycerol ether monooxygenase and it regulates nitric oxide synthase (NOS) activity. Inherited BH4 deficiency leads to hyperphenylalaninemia, and dopamine and neurotransmitter deficiency in the brain. BH4 maintains enzymatic coupling to L-arginine oxidation to produce NO. Oxidation of BH4 to BH2 results in NOS uncoupling, resulting in superoxide (O2.-) formation rather than NO. Superoxide rapidly reacts with NO to produce peroxynitrite which can further uncouple NOS.
These reactive oxygen species (superoxide and peroxynitrite) can contribute to increased oxidative stress in the endothelium leading to atherosclerosis and hypertension (Thony et al. 2000, Crabtree and Channon 2011,Schulz et al. 2008, Schmidt and Alp 2007). The synthesis, recycling and effects of BH4 are shown here. Three enzymes are required for the de novo biosynthesis of BH4 and two enzymes for the recycling of BH4.

Metabolism of vitamins and cofactors

Vitamins are a diverse group of organic compounds, classified according to their solubility, either fat-soluble or water-soluble, that are either not synthesized or synthesized only in limited amounts by human cells. They are required in small amounts in the diet and have distinct biochemical roles, often as coenzymes (cofactors). The physiological processes dependent on vitamin-requiring reactions include many aspects of intermediary metabolism, vision, bone formation, and blood coagulation, and vitamin deficiencies are associated with a correspondingly diverse and severe group of diseases. Metabolic pathways for water-soluble B group and C vitamins, and for fat-soluble vitamins A, D and K are annotated in Reactome, covering processes that convert dietary forms of these molecules into active forms, and that regenerate active forms of vitamin cofactors consumed in other metabolic processes.

Metabolism

Metabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as the inactivation and elimination of toxic ones generated endogenously or present in the extracellular environment. The processes of energy metabolism can be classified into two groups according to whether they involve carbohydrate-derived or lipid-derived molecules, and within each group it is useful to distinguish processes that mediate the breakdown and oxidation of these molecules to yield energy from ones that mediate their synthesis and storage as internal energy reserves. Synthetic reactions are conveniently grouped by the chemical nature of the end products, such as nucleotides, amino acids and related molecules, and porphyrins. Detoxification reactions (biological oxidations) are likewise conveniently classified by the chemical nature of the toxin.

At the same time, all of these processes are tightly integrated. Intermediates in reactions of energy generation are starting materials for biosyntheses of amino acids and other compounds, broad-specificity oxidoreductase enzymes can be involved in both detoxification reactions and biosyntheses, and hormone-mediated signaling processes function to coordinate the operation of energy-generating and energy-storing reactions and to couple these to other biosynthetic processes.