Exploring the Mystery of the Tetrahydrobiopterin Synthetic Defect Lethal Mutant leml from Birth to Death in the Silkworm Bombyx mori

Abstract

Tetrahydrobiopterin (BH4) is a vital coenzyme for several enzymes involved in diverse enzymatic reactions in animals, and BH4 deficiency can lead to metabolic and neurological disorders due to dysfunction in its metabolism. In the silkworm natural homozygous mutant leml, the key enzyme sepiapterin reductase (BmSPR) in the de novo synthesis pathway of BH4 is inactivated, resulting in severe deficiency of BH4 synthesis. However, it is not known why the leml larvae can survive to the second-instar stage and which pathways lead to their death when BH4 is deficient. Here, we quantified BH4 and found that the fertilized eggs contained large amounts of BH4 transferred from the mother to the offspring, maintaining its normal development in the embryo and the first instar. Subsequently, we investigated the multiple pathways in which BH4 is involved as a cofactor. The results showed that BH4 deficiency in silkworms blocked the melanin synthesis pathway, caused an insufficient degree of epidermal sclerosis, disordered tyrosine metabolism, and damaged mitochondria. On the other hand, BH4 deficiency led to the uncoupling of nitric oxide synthase (BmNOS), a reduced NO production, and a significantly reduced fat in fat body catalyzation by phospholipase A2, resulting in an impaired immune system. Meanwhile, the uncoupling of BmNOS increased the O2− content, damaged the DNA, and caused the apoptosis of the body cells. Taken together, BH4 is critical for the life and death of leml mutants. This study lays a foundation for the further exploration of lepidopteran insects and provides an important basis for the treatment of human BH4 deficiency-related diseases.

Tetrahydrobiopterin as a Trigger for Vitiligo: Phototransformation during UV Irradiation

“…The type-I sensitization mechanism is a part of the free radical chain process of both H 4 Bip autoxidation ("dark" reactions) and photooxidation (Table 1). (13) chain termination −48.9…”

“…The occurrence of disorders of melanogenesis in melanocytes, apparently, is associated with the functioning of tetrahydrobiopterin (H 4 Bip), which is a coenzyme of phenylalanine hydroxylase (phenylalanine-4-monooxygenase, EC 1.14.16.1) [1,2,[8][9][10][11][12][13][14]. In melanocytes, tyrosine is formed during the hydroxylation of phenylalanine with the participation of the H 4 Bip coenzyme; then, tyrosine is converted to dihydroxyphenylalanine (DOPA) by tyrosinase (EC 1.14.18.1), and then dopachrome is formed on the way to melanin (Figure 1).…”