Vitamin A and its derivatives play a central role in the vertebrate and invertebrate visual cycle.
1 Retinoids function as the chromophores of the various visual pigments in animals, and photoisomerization of 11-
cis-retinal to all-
trans-retinal is the initiating event in vision.
2 In addition, their importance in development and gene regulation through all-
trans and 9-
cis isomers of retinoic acid (RA) cannot be ignored. Although RA may be formed by successive oxidation of systemically supplied all-
trans-retinol (through serum retinol-binding protein [RBP]), it is possible that oxidation of all-
trans-retinal made in situ by cleavage of β-carotene is a local source of RA in tissues where β-carotene is stored. Because animals are unable to synthesize vitamin A de novo, they acquire their supply of vitamin A either as provitamin A carotenoids (β-carotene and some other carotenoids) from plants or as preformed retinoids in the form of retinyl esters from animal sources.
3 β-Carotene 15,15′ monooxygenase (β-CM) cleaves β-carotene into two molecules of all-
trans-retinal, which are subsequently metabolized into all-
trans-retinol and thence to all-
trans-retinyl esters or to all-
trans-RA. β-Carotene cleavage activity has been reported highest in the intestinal mucosa and is at high levels in liver, kidney, lung, and fat tissues.
4 5 This activity was originally described as a dioxygenase
6 but now has been shown mechanistically to be a monooxygenase.
7 Although the enzymatic activity has been known for many decades,
6 the molecular identity of the protein involved has only recently been determined. β-CM is a member of a family that includes RPE65, a protein required for the regeneration of the 11-
cis-retinal chromophore of rhodopsin,
8 maize VP14, a 9-
cis-epoxycarotenoid cleavage enzyme
9 necessary in the synthesis of the plant hormone abscisic acid and bacterial lignostilbene dioxygenase,
10 which cleaves lignostilbene, a model lignin compound, into two molecules of vanillin. β-CM was originally identified by the use of VP14
9 or RPE65
11 12 as a basis for expressed sequence tag (EST) and genomic searches
13 14 15 16 and by sequencing of partially purified protein with carotene cleavage activity from chicken small intestine.
5 β-CMs were first described in
Drosophila melanogaster 13 17 and chicken
5 and later in mammals.
14 15 16 In addition, von Lintig et al.
17 have determined that the
Drosophila visual mutant
ninaB, which exhibits reduced visual sensitivity and an abnormal ERG, is due to a mutation in the β-CM gene that prevents the cleavage of β-carotene into all-
trans-retinal, the obligate source of chromophore for opsin in the insectan compound eye.