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    • Normally the activity of the lyase increases with the

    2024-05-03

    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 jak stat inhibitor deficiency, which jak stat inhibitor 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.