The role of enzyme compartmentalization on the regulation of steroid synthesis.

ABSTRACT

Steroidogenic enzymes can be compartmentalized at different levels, some by virtue of being membrane bound in specific intra-cellular compartments. Although both 3ß-hydroxysteroid dehydrogenase/Δ(5)-Δ(4) isomerase (3ß-HSD) and 17α-hydroxylase/17,20-lyase cytochrome P450 (P450c17) are expressed in the endoplasmic reticulum (ER) membrane, these proteins may still be spatially separated within this membrane system. Side chain cleavage cytochrome P450 (P450scc) is anchored to the inner mitochondrial membrane and this organelle is the major source of pregnenolone (P5) feeding steroidogenesis. Furthermore, steroidogenic enzymes can also be partitioned in different cells. Although well recognized, the effect of enzyme compartmentalization on the rate of steroid production and the balance of different steroids is unclear. This study uses mathematical modeling to investigate the effect of enzyme compartmentalization on steroid synthesis in a human-ovine-bovine model of steroid synthesis. The study shows that the spatial separation of steroidogenic enzymes within the ER has a minimal effect on the rate of steroid synthesis. The compartmentalization of the enzymes into different organelles of a cell creates cellular steroid gradients and can affect the balance of the different steroid products. The partitioning of steroidogenic enzymes in different cells reduces the rate of steroid synthesis. The greater is the distance between the cells that contain different enzymes, the more the rate of steroid synthesis is reduced. Additionally, when 3ß-HSD is not in the same cell with P450scc (the P5 source) and P450c17, the ratio of the Δ(5)-pathway products' concentrations to the Δ(4)-pathway products' concentrations is increased. However, none of these levels of compartmentalization of steroidogenic enzymes alter the qualitative behaviors of steroid synthesis in response to variation in an enzyme activity or P5 supply.