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  • Normally the activity of the lyase increases with the

    2023-12-08

    Normally, the activity of the 17,20-lyase increases with the onset of adrenarche [7], [8], [15]. Adrenarche has previously been perceived as a relatively sudden event, occurring physiologically between 6 and 8years of age. However, results from our laboratory clearly indicated that adrenarche is a continuous developmental process, starting with a detectable increase in the excretion of DHEA and related androgenic steroids at least as early as 3years of age [11]. Our results of the assessment of the 17,20-lyase activity in controls were consistent with this. In contrast, patients with 21-OHD exhibit a relatively high 17,20-lyase activity even in the neonatal period. This is consistent with our published data that increased androgen pathway activities in neonates and infants with 21-OHD were demonstrated for the backdoor and the classic Δ4 pathways [4]. Additionally to higher ACTH in 21OHD patients due to the MK 886 deficiency, which will induce more CYP17A1, there are two possible explanations why patients with 21-OHD show a higher 17,20-lyase activity. First, CYP17A1 has a high apparent Michaelis–Menten constant (Km) for 17-OHP [5], [7]. Therefore, significant androgen biosynthesis via the Δ4 pathway occurs only in the presence of high 17-OHP concentrations as in 21-OHD. However, after the first year of life, the Δ5 pathway activity in patients with 21-OHD additionally increased [4]. Second, the P450 oxidoreductase (POR) is the electron donor for all microsomal P450 enzymes, including the steroidogenic enzymes CYP17A1 and CYP21A2 [7], [8], [15]. Therefore, both steroidogenic enzymes are rivals for receiving electrons from POR. We speculate that in cases of 21-OHD, the flux of electrons from POR to CYP17A1 would increase and this would lead to a higher 17,20-lyase activity. Additionally to the regulatory influence of the 17,20-lyase on the flux through the backdoor pathway, it is the qualitative regulator that determines which androgen synthesis pathway, e.g. Δ5, Δ4 or backdoor, would be active (Fig. 4A-C). The 17,20-lyase activity of CYP17A1 promotes the conversion of 17-OHP to Δ4A and of 17OH-Preg to DHEA in the classical Δ4 and Δ5 pathways [7], [8], as well as the conversion of 5α-17HP to An in the backdoor pathway [2], [3], [4]. Importantly, 5α-17HP is the best known substrate for the 17,20-lyase [6]. Cytochrome b5 stimulates the 17,20-lyase reaction for the classical Δ5 pathway, i.e. DHEA generation, by over 10-fold. Cytochrome b5 promotes the association of CYP17A1 with POR to increase the efficiency of electron donation from POR [6], [7], [8]. In contrast to the classical pathway, CYP17A1 rapidly converts 5α-17HP to An in the backdoor pathway even in the absence of cytochrome b5, and the addition of cytochrome b5 stimulates the 17,20-lyase reaction only three fold [6]. As a consequence, in a milieu of low cytochrome b5 expression as found in the first year of life before onset of adrenarche, the androgen flux would favour the backdoor pathway, as previously demonstrated [4]. In contrast, in a milieu of high cytochrome b5 expression as found after the onset of adrenarche, the androgen flux through the Δ5 pathway would increase the most [4]. Therefore, the different affinities of CYP17A1 for its three substrates 17-OH-Preg, 17-OHP and 5α-17HP, the level of cytochrome b5 expression in concert with the different responses of the three 17,20-lyase reactions (i.e. classical Δ4, Δ5 and backdoor pathways) to cytochrome b5 regulates the androgenic flux in patients with 21-OHD (Fig. 4). In conclusion, we have demonstrated how the activities of the 5α-reductase and 17,20-lyase influence the flux through the backdoor pathway, and how their activities determine which pathway of androgen synthesis would be active (Fig. 4). The 5α-reductase is the gatekeeper to the backdoor pathway and regulates its activity up to the generation of the key C21 intermediate 5α-17HP. Thereafter, the flux through this alternative route, i.e. the generation of An, is modulated by 17,20-lyase. Neonates with 21-OHD demonstrated a moderate activity of the 5α-reductase. Due to high 17,20-lyase activity, 5α-17HP is converted substantially to An. During infancy, the activity of 5α-reductase is very high, leading to a high activity of the alternative backdoor pathway until the generation of 5α-17HP. Only a moderate An production is the result of low 17,20-lyase activity. After infancy, the activity of the 17,20-lyase of the classic and backdoor pathways increased with increasing age, whereas the 5α-reductase activity decreased, leading to a diminished role of the alternative backdoor pathway for androgenic steroid production.