scholarly journals Homozygous Disruption of P450 Side-Chain Cleavage (CYP11A1) Is Associated with Prematurity, Complete 46,XY Sex Reversal, and Severe Adrenal Failure

2005 ◽  
Vol 90 (1) ◽  
pp. 538-541 ◽  
Author(s):  
Olaf Hiort ◽  
Paul-Martin Holterhus ◽  
Ralf Werner ◽  
Christine Marschke ◽  
Ute Hoppe ◽  
...  
Keyword(s):  
Molecular Genetic ◽  
Laboratory Data ◽  
Sex Reversal ◽  
Molecular Genetic Analysis ◽  
Side Chain ◽  
Steroid Synthesis ◽  
Cytochrome P450scc ◽  
Side Chain Cleavage ◽  
Fetal Survival ◽  
Chain Cleavage

Abstract Disruption of the P450 side-chain cleavage cytochrome (P450scc) enzyme due to deleterious mutations of the CYP11A1 gene is thought to be incompatible with fetal survival because of impaired progesterone production by the fetoplacental unit. We present a 46,XY patient with a homozygous disruption of CYP11A1. The child was born prematurely with complete sex reversal and severe adrenal insufficiency. Laboratory data showed diminished or absent steroidogenesis in all pathways. Molecular genetic analysis of the CYP11A1 gene revealed a homozygous single nucleotide deletion leading to a premature termination at codon position 288. This mutation will delete highly conserved regions of the P450scc enzyme and thus is predicted to lead to a nonfunctional protein. Both healthy parents were heterozygous for this mutation. Our report demonstrates that severe disruption of P450scc can be compatible with survival in rare instances. Furthermore, defects in this enzyme are inherited in an autosomal-recessive fashion, and heterozygote carriers can be healthy and fertile. The possibility of P450scc-independent pathways of steroid synthesis in addition to the current concept of luteoplacental shift of progesterone synthesis in humans has to be questioned.

Evidence That Nonbilayer Phase Propensity of the Membrane Is Important for the Side Chain Cleavage Activity of Cytochrome P450SCC (CYP11A1)†

Biochemistry ◽  
1997 ◽  
Vol 36 (46) ◽  
pp. 14262-14270 ◽  
Author(s):  
Dieter Schwarz ◽  
Pyotr Kisselev ◽  
Wolfgang Pfeil ◽  
Sandra Pisch ◽  
Uwe Bornscheuer ◽  
...  
Keyword(s):  
Side Chain ◽  
Cytochrome P450scc ◽  
Side Chain Cleavage ◽  
Cleavage Activity ◽  
Chain Cleavage

scholarly journals An Outer Mitochondrial Translocase, Tom22, Is Crucial for Inner Mitochondrial Steroidogenic Regulation in Adrenal and Gonadal Tissues

2016 ◽  
Vol 36 (6) ◽  
pp. 1032-1047 ◽  
Author(s):  
Maheshinie Rajapaksha ◽  
Jasmeet Kaur ◽  
Manoj Prasad ◽  
Kevin J. Pawlak ◽  
Brendan Marshall ◽  
...  
Keyword(s):  
Side Chain ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Enzyme ◽  
Steroid Synthesis ◽  
Cytochrome P450scc ◽  
Chain Cleavage ◽  
Cleavage Enzyme ◽  
Terminal Amino ◽  
Interfering Rna ◽  
Amino Acid Segment

After cholesterol is transported into the mitochondria of steroidogenic tissues, the first steroid, pregnenolone, is synthesized in adrenal and gonadal tissues to initiate steroid synthesis by catalyzing the conversion of pregnenolone to progesterone, which is mediated by the inner mitochondrial enzyme 3β-hydroxysteroid dehydrogenase 2 (3βHSD2). We report that the mitochondrial translocase Tom22 is essential for metabolic conversion, as its knockdown by small interfering RNA (siRNA) completely ablated progesterone conversion in both steroidogenic mouse Leydig MA-10 and human adrenal NCI cells. Tom22 forms a 500-kDa complex with mitochondrial proteins associated with 3βHSD2. Although the absence of Tom22 did not inhibit mitochondrial import of cytochrome P450scc (cytochrome P450 side chain cleavage enzyme) and aldosterone synthase, it did inhibit 3βHSD2 expression. Electron microscopy showed that Tom22 is localized at the outer mitochondrial membrane (OMM), while 3βHSD2 is localized at the inner mitochondrial space (IMS), where it interacts through a specific region with Tom22 with its C-terminal amino acids and a small amino acid segment of Tom22 exposed to the IMS. Therefore, Tom22 is a critical regulator of steroidogenesis, and thus, it is essential for mammalian survival.

scholarly journals A role for calmodulin in the regulation of steroidogenesis

1981 ◽  
Vol 90 (2) ◽  
pp. 402-407 ◽  
Author(s):  
PF Hall ◽  
S Osawa ◽  
CL Thomasson
Keyword(s):  
Cyclic Amp ◽  
Adrenal Tumor ◽  
Side Chain ◽  
Dibutyryl Cyclic Amp ◽  
Steroid Production ◽  
Steroid Synthesis ◽  
Side Chain Cleavage ◽  
Cleavage Activity ◽  
Chain Cleavage

Two approaches were used to study the possible role of calmodulin in the regulation of steroid synthesis by mouse adrenal tumor cells: trifluoperazine was used as an inhibitor of calmodulin and liposomes were used to deliver calmodulin into the cells. Trifluoperazine inhibits three steroidogenic responses to both ACTH and dibutyryl cyclic AMP: (a) increase in steroid production, (b) increased transport of cholesterol to mitochondria, and (c) increased side-chain cleavage by mitochondria isolated from cells incubated with ACTH or dibutyryl cyclic AMP. When calmodulin is introduced into the cells via liposomes, steroid synthesis is slightly stimulated. When calmodulin extensively dialyzed against EGTA, this stimulation is abolished. Ca(2+) introduced via liposomes was also without effect. However, when both calmodulin and Ca(2+) are introduced via liposomes (either in separate liposomes or in the same liposomes), steroid synthesis is stimulated. This stimulation does not occur when either anticalmodulin antibodies or EGTA is also present in the liposomes or when trifluoperazine is present in the incubation medium. Calmodulin and Ca(2+) presented together in liposomes to the cells stimulate transport of cholesterol to mitochondria, and side-chain cleavage activity is greater in mitochondria isolated from cells previously fused with liposomes containing calmodulin and Ca(2+) than in mitochondria from cells fused with liposomes containing buffer only. These observations suggest that calmodulin may be involved in regulating the transport of cholesterol to mitochondria, a process which is stimulated by ACTH and dibutyryl cyclic AMP and which may account, at least in part, for the increase in steroid synthesis produced by these agents.

P450 side-chain cleavage enzyme autoantibodies in canine Addison's disease

2013 ◽  
pp. 1-1
Author(s):  
Alisdair Boag ◽  
Kerry McLaughlin ◽  
Mike Christie ◽  
Peter Graham ◽  
Harriet Syme ◽  
...  
Keyword(s):  
Addison’S Disease ◽  
Side Chain ◽  
Addison's Disease ◽  
Side Chain Cleavage ◽  
Chain Cleavage ◽  
Cleavage Enzyme
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