Human Biochemistry Volume 1 - Murray R. 1993

Metabolism of Proteins and Amino Acids
Conversion of Amino Acids into Specialized Products
Melanins

Eumelanins are insoluble, heterogeneous, high-molecular-weight heteropolymers (black or brown in color) composed of 5,6-dihydroxyindole and several of its biosynthetic precursors. Pheomelanins are yellow or reddish-brown polymers with a high molecular weight, yet they are soluble in dilute alkalis. Low-molecular-weight trichochromes closely resemble pheomelanins (both types of compounds are derived from Cysteine and dopachrome). Pheomelanins and trichochromes are predominantly found in Hair and feathers.

Biosynthesis of Melanins

The Structure/133.html">Discussion of melanin biosynthesis is complicated by its multi-step and branched nature, the premature termination of biosynthetic pathways, the complex Chemical Structure of melanin heteropolymers, and their insolubility. These same factors hinder the determination of their structure. Melanins are synthesized in melanosomes—membrane-bound Organelles located within melanocytes, which are Cells that originate from the neural crest during Embryogenesis. The growing eumelanin polymer is believed to be capable of scavenging free radicals; it may also undergo partial degradation by H₂O₂ generated during auto-oxidation processes. Pheomelanins and eumelanins form complexes with the Proteins of the melanosomal matrix, yielding a melanoprotein.

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Fig. 32.9. Known intermediates and reactions in The biosynthesis of eumelanins and pheomelanins. Melanin polymers contain both eumelanin and pheomelanin in varying proportions. Dashed arrows originate from compounds involved in eumelanin synthesis. Circulated numbers indicate probable regulation sites in the biosynthetic pathway. Reaction 1, catalyzed by tyrosinase, is defective in tyrosinase-negative oculocutaneous albinism.

Figure 32.9 summarizes the biosynthetic pathways of eumelanins and pheomelanins, indicating the intermediates formed along the way. The initial reaction is catalyzed by tyrosinase, a copper-containing enzyme. The tyrosinase-catalyzed reaction is impaired in tyrosinase-negative oculocutaneous albinism (see below).

Metabolic Disorders of Melanin Biosynthesis

Given the large number of reactions involved in melanin biosynthesis, it is reasonable to expect that metabolic disorders of melanin production can result from Mutations in various genes.

The term "albinism" encompasses a broad spectrum of clinical syndromes characterized by hypomelanosis, which arises from hereditary defects in the pigment cells (melanocytes) of the eyes and Skin. Several animal models of albinism have been developed using rodents.

The clinical hallmark common to all 10 forms of human oculocutaneous albinism is reduced pigmentation of the eyes and skin. The various forms are differentiated based on clinical, biochemical, ultrastructural, and genetic characteristics. With the exception of a dominant form, all Other types of albinism are inherited in an autosomal recessive manner.

Patients with tyrosinase-negative albinism completely lack ocular pigment. Hair bulbs from these individuals are incapable of converting Tyrosine into pigment in vitro, and their melanocytes contain unpigmented melanosomes. Patients with tyrosinase-positive albinism possess a small amount of ocular pigment, although blonde children may completely lack it. In such cases, hair color can vary from light yellow to light brown, and the skin may present lightly pigmented moles. Melanocytes from the hair bulbs may contain lightly pigmented melanosomes capable of converting tyrosine into black eumelanin in vitro.

Ocular albinism is inherited in an autosomal recessive or X-linked manner. In the latter case, as well as in heterozygotes (but not in Autosomal Recessive Inheritance), melanocytes contain macromelanosomes. In female carriers of X-linked ocular albinism (Nettleship-Falls type), the retina exhibits a mosaic pattern of pigmentation due to random X-chromosome inactivation. The metabolic causes leading to hypomelanosis in ocular albinism remain unknown.

Oculocutaneous albinoidism is inherited as an autosomal recessive trait. With rare exceptions, patients do not exhibit congenital nystagmus, and the condition is typically characterized by photophobia and reduced visual acuity.