Tetrahydrobiopterin biosynthesis, regeneration and functions

Abstract

Tetrahydrobiopterin (BH(4)) cofactor is essential for various processes, and is present in probably every cell or tissue of higher organisms. BH(4) is required for various enzyme activities, and for less defined functions at the cellular level. The pathway for the de novo biosynthesis of BH(4) from GTP involves GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase. Based on gene cloning, recombinant expression, mutagenesis studies, structural analysis of crystals and NMR studies, reaction mechanisms for the biosynthetic and recycling enzymes were proposed. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I, the expression of which may be under the control of cytokine induction. In the liver at least, activity is inhibited by BH(4), but stimulated by phenylalanine through the GTP cyclohydrolase I feedback regulatory protein. The enzymes that depend on BH(4) are the phenylalanine, tyrosine and tryptophan hydroxylases, the latter two being the rate-limiting enzymes for catecholamine and 5-hydroxytryptamine (serotonin) biosynthesis, all NO synthase isoforms and the glyceryl-ether mono-oxygenase. On a cellular level, BH(4) has been found to be a growth or proliferation factor for Crithidia fasciculata, haemopoietic cells and various mammalian cell lines. In the nervous system, BH(4) is a self-protecting factor for NO, or a general neuroprotecting factor via the NO synthase pathway, and has neurotransmitter-releasing function. With regard to human disease, BH(4) deficiency due to autosomal recessive mutations in all enzymes (except sepiapterin reductase) have been described as a cause of hyperphenylalaninaemia. Furthermore, several neurological diseases, including Dopa-responsive dystonia, but also Alzheimer's disease, Parkinson's disease, autism and depression, have been suggested to be a consequence of restricted cofactor availability.

Molybdenum cofactor biosynthesis and deficiency

“…MPT is the only four-carbon side chain-substituted pterin known so far, while several other pteridines, such a biopterin, have three-carbon side chains [65]. Two major pathways are known for the synthesis of pteridines [65] and fl avines [66] [68] confi rmed that each carbon atom of the ribose and the ring carbons of the guanine are incorporated into precursor Z.…”

“…Two major pathways are known for the synthesis of pteridines [65] and fl avines [66] [68] confi rmed that each carbon atom of the ribose and the ring carbons of the guanine are incorporated into precursor Z. A model favored by two labs [67,68] involves a ring-opening reaction followed by the subsequent protein-assisted transfer of the C8 formyl group [41].…”

Neuropsychiatric symptoms and intelligence quotient in autosomal dominant Segawa disease

“…Patients heterozygous for GCH1 mutations/deletions develop a dopa-responsive dystonia (DRD) named autosomal dominant GTPCH (adGTPCH) deficiency (OMIM 128230). GTPCH catalyzes the first and rate-limiting step in the synthesis of tetrahydrobiopterin (BH 4 ) [28]. Segawa disease due to adGTPCH deficiency causes a BH 4 deficiency that leads to decreased dopamine and serotonin biosynthesis, and it has an estimated prevalence of 0.5 per million [23].…”

Cofactors

“…Whereas tetrahydrobiopterin is biosynthesized from GTP via just three enzymecatalyzed steps (2), some coenzyme biosynthetic pathways are characterized by enormous complexity. Thus, the biosynthesis of vitamin B 12 requires five enzymes for the biosynthesis of the precursor uroporhyrinogen III (16) from succinyl-CoA (10) and glycine (11) that is then converted into vitamin B 12 via the sequential action of about 20 enzymes (3).…”