Dehydrocholesterol reductase

Dehydrocholesterol Reductase Deficiency, Smith-Lemli-Opitz syndrome (SLOS)... 

This is one of the few disorders identified that affect enzymes upstream of cholesterol [37]. 7-Dehydrocholesterol reductase (DHCR7) catalyzes probably the last step in cholesterol synthesis, its formation from 7-dehydrocholesterol (7DHC). Reduced... 

Fig. 5.3.6 Diagnose of Smith-Lemli-Opitz syndromesyndrome (SLOS). Urinary dehydropreg-nanetriols (DHPT 5/ -pregn-7-ene-3a,17a,20a-triol and 5j3-pregn-8-ene-3a,17a,20a-triol) partially replace PT in 7-dehydrocholesterol reductase deficiency and can be used to diagnose SLOS. The ratio of DHPT/PT correlates with dehydrocholesterol (DHC)/cholesterol (C) in affected patients (n = 34) and also correlates with clinical severity...

Shackleton CH, Roitman E, Kelley R (1999) Neonatal urinary steroids in Smith-Lemli-Opitz syndrome associated with 7-dehydrocholesterol reductase deficiency. Steroids 64 481-490... 

Hydroxysteroid-A -reductase (also known as 7-dehydrocholesterol reductase). 

Sterol-A -isomerase deficiency, known as Conradi-HUnermann syndrome (CDPX2), is an X-linked dominant disorder. Clinical manifestations of this disorder include skeletal abnormalities, chondrodysplasia punctata, craniofacial anomalies, cataracts, and skin abnormalities. The 7-dehydrocholesterol reductase deficiency, known as Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive disorder occurring in about 1 in 20,000 births. Clinical manifestations of affected individuals include craniofacial abnormalities, microcephaly, congenital heart disease, malformation of the limbs, psychomotor retardation, cerebral maldevelopment, and urogenital anomalies. Measurement of 7-dehydrocholesterol in amniotic fluid during second trimester or in neonatal blood specimen has been useful in the identification of the disorder. The sterol-A " -reductase deficiency causes a developmental phenotype similar to SLO syndrome and is associated with accumulation of desmosterol. The inability of de novo fetal synthesis of cholesterol combined with its inadequate transport from the mother to the fetus appears... 

Waterham, H.R., Wanders, R.J. 2000. Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome. Biochim. Biophys. Acta 1529 340-356. 

Fig. 30.1. The pathway of cholesterol biosynthesis. 30. i, Mevalonate kinase 30.2, 3 -hydroxysteroid dehydrogenase of the 4a-methylsterol-4-demethylase complex 30.3, 3 -hydroxysteroid-A, A -isomerase (sterol-A -isomerase) 30.4, 3/ -hydroxysteroid-A - reductase (desmosterol reductase) 30.5, 3 -hydroxysteroid-A -reductase (7-dehydrocholesterol reductase)...

In disorders which affect cholesterol synthesis (e.g, mevalonic aciduria, 7-dehydrocholesterol reductase deficiency [Smith-Lemli-Opitz syndrome]) there may be markedly reduced bile acid synthesis - these disorders are beyond the scope of his chapter. As indicated in section 3, the synthesis of bile acids involves conversion of C27 bile acids (cholestanoic acids) to their C24 analogues (cholanic acids) and this occurs by a process of )5-oxidation in the peroxisomes. Thus defective bile acid synthesis occurs in disorders of peroxisomal yff-oxidation and in disorders of peroxisome biogenesis. These disorders affect pathways other than the bile acid synthesis pathway and are discussed in Chap. 23. 

For example, by using the nanostructure-initiator mass spectrometry, Patti and colleagues [130] detected intact cholesterol and its derivative molecules in situ to provide the first images of brain sterol localization in a knockout mouse model of 7-dehydrocholesterol reductase. Other nanomaterials (e.g silver nanoparticles) have also been used to analyze lipids directly from tissue samples [133], From a thin film of colloidal graphite on rat brain tissue, direct lipid profiling was performed by graphite-assisted laser desorption/ionization mass spectrometry, which allowed to detect 22 HexCer species, whereas only eight HexCer species are detected with MALDI-TOF/MS [132], Chemically selective analysis for HexCer and ST species was successfully obtained. 

BOROHYDRIDE REDUCTION DEHYDROASCORBATE REDUCTASE DEHYDROCHOLESTEROL REDUCTASE 2-DEHYDRO-3-DEOXY-D-GLUCONATE... 

Table II also contains previously unpublished results of experiments In which medium was supplemented with AY-9944, a compound originally developed as a hypocholesterolemic agent due to Its Inhibition of the A -sterol reductase Involved In the conversion of 7-dehydrocholesterol to cholesterol In de novo sterol biosynthesis In mammals (44). In other biological sys ms (bramble suspension cells, algae an yeast), AY-9944 Inhibits A - to A -lsomerases and. In one case, a A -sterol reductase (45-47). When sitosterol-containing media was supplemented with...

Defects of the biosynthesis of cholesterol were not included in the previous edition of this book, because they were practically non-existing . Since the mid-nineties it has been recognized that patients with the Smith-Lemli-Opitz syndrome lack the final enzyme of cholesterol biosynthesis, i.e. 7-de-hydrocholesterol reductase. Consequently the patients have hypocholestero-lemia and accumulate 7-dehydrocholesterol and 8-dehydrocholesterol in their plasma [12]. 

Fig. 30.4. Diagnostic flow chart for Smith-Lemli-Opitz syndrome and related disorders. FIT, failure-to-thrive DHCR7y 3 -hydroxysteroid-A -reductase 7DHC, 7-dehydrocholesterol DHCR24y 3 -hydroxysteroid-A -reductase...

The use of inhibitors acting after squalene cyclization, such as triparanol, the azasterols mentioned above, and AY-9944 (an inhibitor of 7-dehydrocholesterol-A -reductase see Fig. 1) has no practical advantages the decreased cholesterol formation is accompanied by accumulation of steroidal precursors, which are believed to be as atherogenic as cholesterol itself. 

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