Symmetrical Cleavage of 3Carotene

The small intestine is a major site of retinoid metabolism, beginning with the oxidative cleavage of j3-carotene into two molecules of retinaldehyde (Fig. 7.4). The subject of /3-car-otene cleavage has been quite controversial until recently because both symmetric and asymmetric cleavage of j3-carotene has been reported in crude extracts, and at least in some systems, direct formation of retinoic acid from 0-carotene has been observed (4). However, recent breakthroughs in this field have substantially clarified this area. These breakthroughs can be traced to the first identification of a maize cDNA encoding 9-cis epoxy-

Table 7.2 Human Teratogenicity Associated with Systemic Isotretinoin Therapy

Organ

Teratogenicity Observed

Central nervous system

Skull

External ear

Heart and cardiovascular Thymus

Parathyroid gland

Cerebral abnormalities

Cerebellar malformation

Hydrocephalus

Microcephaly

Cranial nerve deficits

Developmental abnormalities

Anotia

Micropinna

Small or absent external auditory canals

Microphthalmia Developmental abnormalities Developmental failure

Functional deficits leading to parathyroid hormone deficiency carotenoid dioxygenase, the enzyme responsible for the production of abscisic acid, a carotenoid cleavage product that functions as an important plant growth regulator (5, 6). Vogt and collaborators used cDNA encoding maize 9-cis epoxycarotenoid dioxygenase as a probe to isolate a metazoan (Drosophila) homolog of this enzyme and showed that the enzyme, symmetrically cleaved p-carotene into two molecules of retinaldehyde (7). Interestingly, mutations in the Drosophila gene, ninaB, encoding this enzyme, cause blindness, because this species (8), like humans, is dependent on retinoid chromophores for rhodopsin-based visual signal transduction (see below). The phenotype associated with this mutant can be rescued by dietary administration of retinal, the direct precursor of the Drosophila visual chro-mophore, 3-hydroxy-retinal (8), thus bypassing the need for dietary sources of carotinoids. Hunziker's group then isolated a cDNA encoding the chicken j8-carotene-15,15'-dioxygen-ase (9), and the groups of Blaner and Cunningham isolated the mouse homolog (10,11) and demonstrated that this enzyme catalyzed the symmetrical cleavage of p-carotene into two molecules of retinaldehyde.

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