Abstract
Ultraviolet A photosensitivity is a debilitating symptom associated with the metabolic disorder Smith-Lemli-Opitz syndrome (SLOS). SLOS is a manifestation of the deficiency of 7-dehydrocholesterol reductase, an enzyme involved in the cholesterol biosynthesis. As a result several abnormal intermediary compounds are formed among which Cholesta 5, 7, 9(11)-trien-3beta-ol is the most likely cause of photosensitivity. The effect of various drugs acting on cholesterol biosynthetic pathway on SLOS is not clear as clinical trials are not available for this rare disorder. A Flux Balance Analysis (FBA) has been carried out using the software CellNetAnalyzer or FluxAnalyzer to gain insight into the probable effects of various drugs acting on cholesterol biosynthetic pathway on photosensitivity in SLOS. The model consisted of 44 metabolites and 40 reactions. The formation flux of Cholesta 5, 7, 9(11)-trien-3beta-ol increased in SLOS and remained unchanged on simulation of the effect of miconazole and SR31747. However zaragozic acid can potentially reduce the flux through the entire pathway. FBA predicts zaragozic acid along with cholesterol supplementation as an effective treatment for photosensitivity in SLOS.
Highlights
The Smith-Lemli-Opitz syndrome (SLOS) is a rare autosomal recessive disorder characterised by multiple congenital abnormalities. [1, 2] SLOS is a manifestation of an abnormality in the late phase of cholesterol biosynthesis due to an inherited deficiency of the enzyme 7dehydrocholesterol-reductase [3]
Though the final stages of cholesterol biosynthesis are adequately described [8], the metabolic fate of 7dehydrocholesterol (7-DHC) which accumulates as a result of the deficiency of its reductase enzyme in SLOS is unclear
Though cholesterol supplementation is found to be useful in relieving photosensitivity [6], the effect of other drugs which act on the final phase of cholesterol biosynthesis on this symptom is unknown
Summary
The Smith-Lemli-Opitz syndrome (SLOS) is a rare autosomal recessive disorder characterised by multiple congenital abnormalities. [1, 2] SLOS is a manifestation of an abnormality in the late phase of cholesterol biosynthesis due to an inherited deficiency of the enzyme 7dehydrocholesterol-reductase [3]. [1, 2] SLOS is a manifestation of an abnormality in the late phase of cholesterol biosynthesis due to an inherited deficiency of the enzyme 7dehydrocholesterol-reductase [3]. Though the final stages of cholesterol biosynthesis are adequately described [8], the metabolic fate of 7dehydrocholesterol (7-DHC) which accumulates as a result of the deficiency of its reductase enzyme in SLOS is unclear. FBA has been used here to understand the behaviour of the final stages of cholesterol biosynthesis in normal and SLOS individuals and to gain insight into the probable effects of drugs acting on this pathway on the symptom of photosensitivity. The flux through R 37 which [16] The mevalonate pathway is highly regulated especially represents the formation of cholesta-5,7,9(11)-trien-3β-ol by feedback inhibition of HMG-CoA reductase by will be indicative of the severity of photosensitivity. Supplementation could be very effective in the management of photosensitivity in SLOS
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