Hepatic Purine Biosynthesis is Stringently Regulated
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p340-341
2025-09-01
452
AMP & GMP Feedback Regulate PRPP Glutamyl Amidotransferase
Biosynthesis of IMP is energetically expensive. In addition to ATP, glycine, glutamine, aspartate, and reduced tetrahydrofolate derivatives all are consumed. Thus, it is of survival advantage to closely regulate purine biosynthesis in response to varying physiologic need. The overall determinant of the rate of de novo purine nucleotide biosynthesis is the concentration of PRPP. This, in turn, depends on the rate of PRPP synthesis, utilization, degradation, and regulation. The rate of PRPP synthesis depends on the availability of ribose 5-phosphate and on the activity of PRPP synthetase, EC 2.7.6.1 (reaction ➁ Figure 1), an enzyme whose activity is feedback inhibited by AMP, ADP, GMP, and GDP. Elevated levels of these nucleoside phosphates thus signal a physiologically appropriate overall decrease in their biosynthesis.
Fig1. Control of the rate of de novo purine nucleotide biosynthesis. Reactions ➀ and ➁ are catalyzed by PRPP synthetase and by PRPP glutamyl amidotransferase, respectively. Solid lines represent chemical flow. Broken red lines represent feedback inhibition by intermediates of the pathway.
AMP & GMP Feedback Regulate Their Formation From IMP
In addition to regulation at the level of PRPP biosynthesis, additional mechanisms that regulate conversion of IMP to ATP and GTP are summarized in Figure2. AMP feedback inhibits adenylosuccinate synthetase, EC 6.3.4.4 (reaction 12, Figure 3), and GMP inhibits IMP dehydrogenase, EC 1.1.1.205 (reaction 14, Figure 33–3). Furthermore, conversion of IMP to adenylosuccinate enroute to AMP (reaction 12, Figure 33–3) requires GTP, and conversion of xanthinylate (XMP) to GMP requires ATP. This cross-regulation between the pathways of IMP metabolism thus serves to balance the biosynthesis of purine nucleoside triphosphates by decreasing the synthesis of one purine nucleotide when there is a deficiency of the other nucleotide. AMP and GMP also inhibit hypoxanthine-guanine phosphoribosyltransferase, which converts hypoxanthine and guanine to IMP and GMP (Figure 4), while GMP also feedback inhibits PRPP glutamyl amidotransferase (reaction ➁, Figure 5).
Fig2. Regulation of the conversion of IMP to adenosine nucleotides and guanosine nucleotides. Solid lines represent chemical flow. Broken green lines represent positive feedback loops , and broken red lines represent negative feedback loops ⊖. (AMPS, adenylosuccinate; XMP, xanthosine monophosphate; their structure are given in figure 3)
Fig3. Conversion of IMP to AMP and GMP
Fig4. Phosphoribosylation of adenine, hypoxanthine, and guanine to form AMP, IMP, and GMP, respectively.
Fig5. Purine biosynthesis from ribose 5-phosphate and ATP. See the text for explanations. ( P , PO3 2– or PO2–.)
الاكثر قراءة في الكيمياء الحيوية
اخر الاخبار
اخبار العتبة العباسية المقدسة
