2777:
1319:
54:. Most of the PDE families are composed of more than one gene. PDE3 is clinically significant because of its role in regulating heart muscle, vascular smooth muscle and platelet aggregation. PDE3 inhibitors have been developed as pharmaceuticals, but their use is limited by arrhythmic effects and they can increase mortality in some applications.
20:
706:(PDE3IK). By blocking insulin activation of PDE3IK, and in turn phosphorylation/activation of PDE3B, the antilipolytic effect of insulin can be antagonized. Activation of PDE3B decreases concentrations of cAMP, which in turn reduces protein kinase A activity. Protein kinase A is responsible for activation of
397:
consists of two members, PDE3A and PDE3B. The PDE3 isoforms are structurally similar, containing an N-terminal domain important for the localization and a C-terminus end. The 44-amino acid insertion in the catalytic domain differs in the PDE3 isoforms, and the N-terminal portions of the isoforms are
825:
The N-terminal portions of PDEs are widely divergent and contain determinants that are associated with regulatory properties specific to different gene families. For PDE3, those determinants are the hydrophobic membrane association domains and cAMP-dependent protein kinase phosphorylation sites.
894:
In the PDEs that have had their structure solved, there seems to be an invariant glutamine residue that stabilizes the binding of the purine ring in the active site (binding pocket). The g-amino group of the glutamine residue can alternatively adopt two different orientations:
872:
When different PDEs were first identified, two types of PDEs (PDE3 and PDE4) that exhibited high affinities for cAMP were isolated. PDE3 exhibited high affinity for both cGMP and cAMP, but PDE4 had high affinity for only cAMP. For that reason, the PDE3 was called the
1278:
Maurice DH, Palmer D, Tilley DG, Dunkerley HA, Netherton SJ, Raymond DR, et al. (September 2003). "Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system".
100:
Both PDE3A and PDE3B are expressed in vascular smooth muscle cells and are likely to modulate contraction. Their expression in vascular smooth muscle is altered under specific conditions such as elevated cAMP and
1317:, Movsesian M, "Isoform-Selective Inhibitors and Activators of PDE3 Cyclic Nucleotide Phosphodiesterases", published 13 February 2003, assigned to University of Utah Technology Transfer Office
444:
In their full-length both PDE3A and PDE3B contain two N-terminal hydrophobic membrane association regions, NHR1 and NHR2 (figure 2). The difference of the PDE3A1-3 variants lies in whether they include:
822:
that can bind to these sites are either zinc or magnesium. The zinc binding site has two histidine and two aspartic acid residues that are absolutely conserved among those PDEs studied to date.
933:
residue and a water molecule, which was initially associated with Mg. A second arginine residue and the Mg may also play roles during binding and/or play roles in the next step
475:
PDE3A is mainly implicated in cardiovascular function and fertility but PDE3B is mainly implicated in lipolysis. Table 1 is an overview of localization of the PDE3 isoforms.
1012:
Aggregation of platelets is highly regulated by cyclic nucleotides. PDE3A is a regulator of this process, and PDE3 inhibitors effectively prevent aggregation of platelets.
760:
The catalytic domain of PDE3 is characterized by a 44-amino acid insert, but this insert is unique to the PDE3 family, and is a factor when determining a structure for a
757:
phosphodiester bonds. It is also believed that it contains family-specific determinants for differences in affinity for substrates and sensitivity for inhibitors.
1063:
in HDM-driven models of allergic airway inflammation. PDE3 inhibitors enoximone and milrinone can be used as a rescue drug in life-threatening bronchial asthma/
277:
137:
1422:
Nazir M, Senkowski W, Nyberg F, Blom K, Edqvist PH, Jarvius M, et al. (December 2017). "Targeting tumor cells based on
Phosphodiesterase 3A expression".
733:
The mammalian PDEs share a common structural organization and contain three functional domains, which include the conserved catalytic core, a regulatory
23:
Figure 1: Role of PDE3 in cAMP- and cGMP-mediated signal transduction. PK-A: Protein kinase A (cAMP dependent). PK-G: Protein kinase G (cGMP-dependent).
914:
From early studies an initial model of PDE, active site topography was derived. This early model can be summarized into the following steps concerning
1851:
1168:
Lugnier C (March 2006). "Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents".
2098:
797:
pocket is formed by residues that are highly conserved among all PDEs. This pocket is the active site and is composed of four subsites :
672:
inhibition as PDE3A. The PDE3B has been extensively studied for its importance in mediating the antilipolytic and antiglycogenlytic effect of
2802:
2797:
2012:
2113:
2107:
1908:
1658:
301:
161:
745:
identity, than between different families. It is believed that the core contains common structural elements that are important for the
656:
both activate PDE3A and PDE3B via phosphorylation at two different phosphorylation sites (P1 and P2) between NHR1 and NHR2 (figure 2).
1956:
2496:
2067:
1856:
1020:
and is thought to involve inhibition of platelet aggregation and also inhibition of smooth muscle proliferation and vasodilation.
906:
In PDEs that can hydrolyse both cGMP and cAMP (PDE3s), the glutamine can rotate freely and therefore switch between orientations.
289:
149:
1051:
PDE3a expression has been described as a biomarker for sensitivity for PDE3-inhibitor
Zardaverine in different types of cancer.
2174:
2062:
1216:"Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development"
282:
142:
1983:
1893:
1846:
950:
5´-AMP is formed as an "inverted" product. Electronic charges conserve the net charge overall and across the transition state
915:
866:
855:
843:
839:
754:
750:
669:
665:
661:
2652:
2405:
2346:
2767:
2450:
2017:
2007:
880:
The 44-amino acid insertion in the catalytic domain of PDE3s is believed to be involved in PDE3's interaction with its
2410:
2302:
1927:
1076:
636:
PDE3A can be either membrane-associated or cytosolic, depending on the variant and the cell type it is expressed in.
1118:
Bender AT, Beavo JA (September 2006). "Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use".
2812:
1996:
1992:
1988:
1904:
1737:
779:
of the catalytic domains of several PDEs, including PDE3B, have shown that they contain three helical subdomains:
2637:
2753:
2740:
2727:
2714:
2701:
2688:
2675:
2258:
2204:
2164:
2123:
2027:
1866:
1834:
1720:
1684:
1017:
2647:
2601:
2544:
1912:
1761:
1675:
881:
2549:
1781:
1651:
1610:"The use of milrinone versus conventional treatment for the management of life-threatening bronchial asthma"
2337:
1976:
987:
765:
761:
611:
525:
503:
67:
294:
154:
2570:
2489:
2272:
2169:
1961:
1922:
1786:
1708:
1060:
626:
403:
347:
207:
86:
2642:
1314:
888:
717:
Whether phosphorylation pathways, which regulate activity of PDE3A or PDE3B, could serve as potential
2455:
2290:
2285:
2218:
1878:
1703:
1387:
Erhardt PW, Chou YL (1991). "A topographical model for the c-AMP phosphodiesterase III active site".
51:
2606:
2310:
2280:
2079:
2003:
1939:
1725:
1064:
699:
586:
2539:
2443:
2295:
1776:
1766:
1644:
1447:
1253:
1143:
79:
47:
43:
2807:
2244:
2189:
2157:
2032:
1751:
1590:
1539:
1498:
1439:
1404:
1369:
1296:
1245:
1185:
1135:
776:
684:
102:
39:
31:
2585:
2580:
2554:
2482:
2320:
1900:
1805:
1800:
1756:
1621:
1580:
1570:
1529:
1488:
1478:
1431:
1396:
1359:
1288:
1235:
1227:
1177:
1127:
945:
769:
653:
649:
425:
is usually dominant. Three different variants of PDE3A (PDE3A1-3) are products of alternate
351:
342:
202:
887:
The proposed molecular mechanism of cyclic nucleotide specificity of PDEs is the so-called
2632:
2616:
2529:
2422:
2236:
2152:
2147:
2142:
2055:
2050:
1810:
1688:
692:
645:
615:
607:
399:
371:
231:
211:
1240:
1215:
1009:. For example, when mice are made completely deficient of PDE3A, they become infertile.
741:. The conserved catalytic core is much more similar within PDE families, with about 80%
2781:
2670:
2611:
2395:
2390:
2385:
1771:
1746:
1742:
1715:
1698:
1585:
1558:
1493:
1466:
959:
82:
1465:
Beute J, Lukkes M, Koekoek EP, Nastiti H, Ganesh K, de Bruijn MJ, et al. (2018).
606:
In general, PDE3 can be either cytosolic or membrane-bound and has been associated to
2791:
2575:
2534:
2136:
2045:
1795:
1400:
1181:
573:
555:
75:
1451:
1348:"Structure, localization, and regulation of cGMP-inhibited phosphodiesterase (PDE3)"
2524:
2263:
2194:
1917:
1838:
1257:
1147:
619:
550:
318:
178:
2748:
2683:
2519:
2438:
2209:
2103:
1966:
1932:
1870:
1636:
1626:
1609:
1575:
1435:
794:
560:
535:
381:
241:
94:
35:
2776:
814:
The M site is at the bottom of the hydrophobic binding pocket and contains two
2415:
1483:
1231:
1013:
858:
746:
742:
738:
734:
688:
657:
545:
530:
325:
185:
2722:
2696:
2328:
2127:
2040:
1667:
1364:
1347:
1036:
711:
630:
580:
509:
464:
90:
71:
1594:
1543:
1502:
1443:
1300:
1249:
1189:
1139:
1408:
1373:
2373:
2368:
2363:
2184:
1819:
1671:
1534:
1517:
1292:
967:
930:
815:
598:*Variants of PDE3A have differential expression in cardiovascular tissues
330:
190:
2380:
2358:
2353:
1971:
1040:
1024:
923:
835:
677:
673:
460:
438:
406:, but the distinction is in expression profiles and affinity for cGMP.
394:
63:
19:
1131:
902:
The hydrogen bond network supports adenine binding – cAMP selectivity.
2735:
2505:
2400:
2333:
2226:
1824:
1732:
1032:
998:
974:
899:
The hydrogen bond network supports guanine binding – cGMP selectivity
722:
707:
703:
696:
540:
519:
514:
313:
173:
1214:
Jeon YH, Heo YS, Kim CM, Hyun YL, Lee TG, Ro S, Cho JM (June 2005).
74:
that inhibit PDE3 were originally investigated for the treatment of
1467:"A pathophysiological role of PDE3 in allergic airway inflammation"
2709:
2342:
2093:
2089:
981:
681:
497:
426:
410:
18:
1059:
Targeting PDE3 with optimal doses and timing, enoximone prevents
2074:
1951:
1944:
1888:
1883:
1028:
819:
718:
625:
PDE3B is predominantly membrane-associated, and is localized to
306:
166:
2478:
1640:
929:
The phosphate atom in cAMP binds to PDE active site, using an
2474:
1518:"Emergency treatment of status asthmaticus with enoximone"
1023:
The most studied roles of PDE3B have been in the areas of
398:
quite divergent. PDE3A and PDE3B have strikingly similar
997:
It has been demonstrated that PDE3A inhibition prevents
2765:
1346:
Degerman E, Belfrage P, Manganiello VC (March 1997).
725:
itself is unclear and beyond the scope of this text.
721:
targets rather than the catalytic domain of the PDE3
884:
and inhibitors, but that remains to be established.
2661:
2625:
2594:
2563:
2512:
2431:
2319:
2271:
2257:
2235:
2217:
2203:
2183:
2122:
2026:
1865:
1833:
1683:
834:At first, the PDE3s were purified and described as
377:
367:
362:
341:
336:
324:
312:
300:
288:
276:
268:
263:
255:
237:
227:
222:
201:
196:
184:
172:
160:
148:
136:
128:
123:
115:
1557:Schulz O, Wiesner O, Welte T, et al. (2020).
1039:in mice, it causes impaired insulin secretion and
1962:Fructose 6-P,2-kinase:fructose 2,6-bisphosphatase
644:PDE3A and PDE3B activity is regulated by several
664:by PDE3 isoforms is also directly inhibited by
596:Table 1: Overview of PDE3 isoform localization.
459:The last can be predicted to be exclusively on
668:, although PDE3B is only ≈10% as sensitive to
2490:
1652:
926:and ribose moieties in an "anti" relationship
34:. The PDEs belong to at least eleven related
8:
1341:
1339:
1337:
1335:
1333:
1331:
1329:
89:any longer. Nonetheless, the PDE3 inhibitor
62:PDE3 enzymes are involved in regulation of
2497:
2483:
2475:
2268:
2214:
2200:
1659:
1645:
1637:
1035:signaling. When PDE3B is overexpressed in
359:
219:
1625:
1584:
1574:
1533:
1492:
1482:
1363:
1273:
1271:
1269:
1267:
1239:
1163:
1161:
1159:
1157:
1113:
1111:
944:O with formation of a trigonal bipyramid
793:At the interface of these domains a deep
714:as well as other physiological pathways.
1109:
1107:
1105:
1103:
1101:
1099:
1097:
1095:
1093:
1091:
702:by an insulin-stimulated protein serine
477:
93:is approved for use in heart failure in
2772:
1852:Ubiquitin carboxy-terminal hydrolase L1
1087:
993:enhance airway smooth muscle relaxation
1209:
1207:
1205:
1203:
1201:
1199:
593:
252:
112:
2432:either deoxy- or ribo-
7:
2013:Protein serine/threonine phosphatase
1220:Cellular and Molecular Life Sciences
2114:Cyclic nucleotide phosphodiesterase
2108:Clostridium perfringens alpha toxin
1909:Tartrate-resistant acid phosphatase
1608:Sobhy A, Eldin DM, Zaki HV (2019).
1352:The Journal of Biological Chemistry
850:values of 0.1–0.8 μM. However the V
409:The PDE3 family is composed of two
1957:Pyruvate dehydrogenase phosphatase
421:. In cells expressing both genes,
14:
1857:4-hydroxybenzoyl-CoA thioesterase
1559:"Enoximone in status asthmaticus"
2775:
1182:10.1016/j.pharmthera.2005.07.003
85:, they are not studied for that
2175:N-acetylglucosamine-6-sulfatase
2063:Sphingomyelin phosphodiesterase
1170:Pharmacology & Therapeutics
818:metal binding sites. The metal
38:, which are different in their
1984:Inositol-phosphate phosphatase
1847:Palmitoyl protein thioesterase
980:increase contractility of the
1:
2347:RNA-induced silencing complex
1016:is approved for treatment of
877:to distinguish it from PDE4.
807:Hydrophobic pocket (H pocket)
783:N-terminal cyclin fold region
687:. The activation of PDE3B in
2803:Genes on human chromosome 11
2798:Genes on human chromosome 12
2451:Serratia marcescens nuclease
2018:Dual-specificity phosphatase
2008:Protein tyrosine phosphatase
1401:10.1016/0024-3205(91)90254-9
589:-associated (predominantly)
1928:Fructose 1,6-bisphosphatase
1627:10.2174/2589645801913010012
1614:Open Anesthesiology Journal
1576:10.1183/23120541.00367-2019
1436:10.1016/j.yexcr.2017.10.032
1077:Oocyte maturation inhibitor
940:2 attack of phosphorus by H
861:is 4–10 times higher than V
801:Metal binding site (M site)
78:, but, because of unwanted
2829:
1424:Experimental Cell Research
568:Intracellular localization
455:neither NHR1 nor the NHR2.
2653:Michaelis–Menten kinetics
2165:Galactosamine-6 sulfatase
1721:6-phosphogluconolactonase
1484:10.1172/jci.insight.94888
1232:10.1007/s00018-005-4533-5
1018:intermittent claudication
789:C-terminal helical bundle
358:
218:
2545:Diffusion-limited enzyme
1913:Purple acid phosphatases
922:cAMP substrate with its
918:active site topography:
1365:10.1074/jbc.272.11.6823
1120:Pharmacological Reviews
492:Localization in tissues
2338:Microprocessor complex
1977:Beta-propeller phytase
1281:Molecular Pharmacology
988:vascular smooth muscle
804:Core pocket (Q pocket)
612:sarcoplasmic reticulum
526:Vascular smooth muscle
504:Vascular smooth muscle
68:vascular smooth muscle
24:
2638:Eadie–Hofstee diagram
2571:Allosteric regulation
2273:Endodeoxyribonuclease
2170:Iduronate-2-sulfatase
1923:Glucose 6-phosphatase
1709:Butyrylcholinesterase
1061:allergic inflammation
810:Lid region (L region)
627:endoplasmic reticulum
22:
2648:Lineweaver–Burk plot
2456:Micrococcal nuclease
2291:Deoxyribonuclease IV
2286:Deoxyribonuclease II
2219:Exodeoxyribonuclease
1879:Alkaline phosphatase
1704:Acetylcholinesterase
1293:10.1124/mol.64.3.533
838:that hydrolyse both
257:phosphodiesterase 3B
117:phosphodiesterase 3A
52:regulation mechanism
2311:UvrABC endonuclease
2281:Deoxyribonuclease I
2004:Protein phosphatase
1940:Protein phosphatase
1738:Bile salt-dependent
1726:PAF acetylhydrolase
1065:acute severe asthma
691:is associated with
471:Tissue distribution
393:The PDE3 family in
2607:Enzyme superfamily
2540:Enzyme promiscuity
2444:Mung bean nuclease
2303:Restriction enzyme
2296:Restriction enzyme
1535:10.1093/bja/aeu048
875:cGMP-inhibited PDE
830:Substrate affinity
449:both NHR1 and NHR2
404:kinetic properties
109:Isoforms and genes
44:substrate affinity
25:
2813:Molecular biology
2763:
2762:
2472:
2471:
2468:
2467:
2464:
2463:
2253:
2252:
2245:Oligonucleotidase
2190:deoxyribonuclease
2158:Steroid sulfatase
2033:Phosphodiesterase
1762:Hormone-sensitive
1569:(1): 00367–2019.
1132:10.1124/pr.58.3.5
777:crystal structure
604:
603:
600:
437:encodes a single
391:
390:
387:
386:
251:
250:
247:
246:
40:primary structure
32:phosphodiesterase
2820:
2780:
2779:
2771:
2643:Hanes–Woolf plot
2586:Enzyme activator
2581:Enzyme inhibitor
2555:Enzyme catalysis
2499:
2492:
2485:
2476:
2321:Endoribonuclease
2307:
2301:
2269:
2215:
2201:
1901:Acid phosphatase
1782:Monoacylglycerol
1692:ester hydrolases
1661:
1654:
1647:
1638:
1632:
1631:
1629:
1605:
1599:
1598:
1588:
1578:
1554:
1548:
1547:
1537:
1528:(6): 1105–1108.
1516:Beute J (2014).
1513:
1507:
1506:
1496:
1486:
1462:
1456:
1455:
1419:
1413:
1412:
1384:
1378:
1377:
1367:
1343:
1324:
1323:
1322:
1318:
1311:
1305:
1304:
1275:
1262:
1261:
1243:
1226:(11): 1198–220.
1211:
1194:
1193:
1165:
1152:
1151:
1115:
946:transition state
889:glutamine switch
710:, which induces
654:protein kinase B
650:Protein kinase A
594:
478:
360:
259:, cGMP-inhibited
253:
220:
119:, cGMP-inhibited
113:
16:Class of enzymes
2828:
2827:
2823:
2822:
2821:
2819:
2818:
2817:
2788:
2787:
2786:
2774:
2766:
2764:
2759:
2671:Oxidoreductases
2657:
2633:Enzyme kinetics
2621:
2617:List of enzymes
2590:
2559:
2530:Catalytic triad
2508:
2503:
2473:
2460:
2427:
2315:
2305:
2299:
2262:
2249:
2237:Exoribonuclease
2231:
2208:
2192:
2188:
2179:
2153:Arylsulfatase L
2148:Arylsulfatase B
2143:Arylsulfatase A
2118:
2031:
2022:
1861:
1829:
1691:
1679:
1665:
1635:
1607:
1606:
1602:
1556:
1555:
1551:
1515:
1514:
1510:
1464:
1463:
1459:
1421:
1420:
1416:
1386:
1385:
1381:
1345:
1344:
1327:
1320:
1313:
1312:
1308:
1277:
1276:
1265:
1213:
1212:
1197:
1167:
1166:
1155:
1117:
1116:
1089:
1085:
1073:
1057:
1049:
960:PDE3 inhibitors
957:
943:
939:
912:
864:
853:
849:
832:
731:
693:phosphorylation
646:phosphorylation
642:
608:plasma membrane
597:
558:
553:
548:
543:
538:
533:
528:
517:
512:
507:
501:
473:
400:pharmacological
111:
70:contractility.
60:
46:, responses to
17:
12:
11:
5:
2826:
2824:
2816:
2815:
2810:
2805:
2800:
2790:
2789:
2785:
2784:
2761:
2760:
2758:
2757:
2744:
2731:
2718:
2705:
2692:
2679:
2665:
2663:
2659:
2658:
2656:
2655:
2650:
2645:
2640:
2635:
2629:
2627:
2623:
2622:
2620:
2619:
2614:
2609:
2604:
2598:
2596:
2595:Classification
2592:
2591:
2589:
2588:
2583:
2578:
2573:
2567:
2565:
2561:
2560:
2558:
2557:
2552:
2547:
2542:
2537:
2532:
2527:
2522:
2516:
2514:
2510:
2509:
2504:
2502:
2501:
2494:
2487:
2479:
2470:
2469:
2466:
2465:
2462:
2461:
2459:
2458:
2453:
2448:
2447:
2446:
2435:
2433:
2429:
2428:
2426:
2425:
2420:
2419:
2418:
2413:
2408:
2403:
2393:
2388:
2383:
2378:
2377:
2376:
2371:
2366:
2361:
2351:
2350:
2349:
2340:
2325:
2323:
2317:
2316:
2314:
2313:
2308:
2293:
2288:
2283:
2277:
2275:
2266:
2255:
2254:
2251:
2250:
2248:
2247:
2241:
2239:
2233:
2232:
2230:
2229:
2223:
2221:
2212:
2198:
2181:
2180:
2178:
2177:
2172:
2167:
2162:
2161:
2160:
2155:
2150:
2145:
2132:
2130:
2120:
2119:
2117:
2116:
2111:
2101:
2096:
2087:
2082:
2077:
2072:
2071:
2070:
2060:
2059:
2058:
2053:
2043:
2037:
2035:
2024:
2023:
2021:
2020:
2015:
2010:
2001:
2000:
1999:
1981:
1980:
1979:
1969:
1964:
1959:
1954:
1949:
1948:
1947:
1937:
1936:
1935:
1925:
1920:
1915:
1898:
1897:
1896:
1891:
1886:
1875:
1873:
1863:
1862:
1860:
1859:
1854:
1849:
1843:
1841:
1831:
1830:
1828:
1827:
1822:
1816:
1815:
1814:
1813:
1808:
1803:
1792:
1791:
1790:
1789:
1787:Diacylglycerol
1784:
1779:
1774:
1769:
1764:
1759:
1754:
1749:
1740:
1729:
1728:
1723:
1718:
1716:Pectinesterase
1713:
1712:
1711:
1706:
1699:Cholinesterase
1695:
1693:
1681:
1680:
1666:
1664:
1663:
1656:
1649:
1641:
1634:
1633:
1600:
1549:
1508:
1457:
1430:(2): 308–315.
1414:
1379:
1358:(11): 6823–6.
1325:
1306:
1263:
1195:
1153:
1126:(3): 488–520.
1086:
1084:
1081:
1080:
1079:
1072:
1069:
1056:
1053:
1048:
1045:
995:
994:
991:
984:
978:
971:
956:
953:
952:
951:
948:
941:
937:
934:
927:
911:
908:
904:
903:
900:
862:
851:
847:
831:
828:
812:
811:
808:
805:
802:
791:
790:
787:
784:
730:
727:
641:
638:
602:
601:
591:
590:
583:
570:
564:
563:
522:
494:
488:
487:
484:
481:
472:
469:
457:
456:
453:
450:
389:
388:
385:
384:
379:
375:
374:
369:
365:
364:
356:
355:
345:
339:
338:
334:
333:
328:
322:
321:
316:
310:
309:
304:
298:
297:
292:
286:
285:
280:
274:
273:
270:
266:
265:
261:
260:
249:
248:
245:
244:
239:
235:
234:
229:
225:
224:
216:
215:
205:
199:
198:
194:
193:
188:
182:
181:
176:
170:
169:
164:
158:
157:
152:
146:
145:
140:
134:
133:
130:
126:
125:
121:
120:
110:
107:
59:
56:
15:
13:
10:
9:
6:
4:
3:
2:
2825:
2814:
2811:
2809:
2806:
2804:
2801:
2799:
2796:
2795:
2793:
2783:
2778:
2773:
2769:
2755:
2751:
2750:
2745:
2742:
2738:
2737:
2732:
2729:
2725:
2724:
2719:
2716:
2712:
2711:
2706:
2703:
2699:
2698:
2693:
2690:
2686:
2685:
2680:
2677:
2673:
2672:
2667:
2666:
2664:
2660:
2654:
2651:
2649:
2646:
2644:
2641:
2639:
2636:
2634:
2631:
2630:
2628:
2624:
2618:
2615:
2613:
2612:Enzyme family
2610:
2608:
2605:
2603:
2600:
2599:
2597:
2593:
2587:
2584:
2582:
2579:
2577:
2576:Cooperativity
2574:
2572:
2569:
2568:
2566:
2562:
2556:
2553:
2551:
2548:
2546:
2543:
2541:
2538:
2536:
2535:Oxyanion hole
2533:
2531:
2528:
2526:
2523:
2521:
2518:
2517:
2515:
2511:
2507:
2500:
2495:
2493:
2488:
2486:
2481:
2480:
2477:
2457:
2454:
2452:
2449:
2445:
2442:
2441:
2440:
2437:
2436:
2434:
2430:
2424:
2421:
2417:
2414:
2412:
2409:
2407:
2404:
2402:
2399:
2398:
2397:
2394:
2392:
2389:
2387:
2384:
2382:
2379:
2375:
2372:
2370:
2367:
2365:
2362:
2360:
2357:
2356:
2355:
2352:
2348:
2344:
2341:
2339:
2335:
2332:
2331:
2330:
2327:
2326:
2324:
2322:
2318:
2312:
2309:
2304:
2297:
2294:
2292:
2289:
2287:
2284:
2282:
2279:
2278:
2276:
2274:
2270:
2267:
2265:
2260:
2256:
2246:
2243:
2242:
2240:
2238:
2234:
2228:
2225:
2224:
2222:
2220:
2216:
2213:
2211:
2206:
2202:
2199:
2196:
2191:
2186:
2182:
2176:
2173:
2171:
2168:
2166:
2163:
2159:
2156:
2154:
2151:
2149:
2146:
2144:
2141:
2140:
2139:
2138:
2137:arylsulfatase
2134:
2133:
2131:
2129:
2125:
2121:
2115:
2112:
2109:
2105:
2102:
2100:
2097:
2095:
2091:
2088:
2086:
2083:
2081:
2078:
2076:
2073:
2069:
2066:
2065:
2064:
2061:
2057:
2054:
2052:
2049:
2048:
2047:
2046:Phospholipase
2044:
2042:
2039:
2038:
2036:
2034:
2029:
2025:
2019:
2016:
2014:
2011:
2009:
2005:
2002:
1998:
1994:
1990:
1987:
1986:
1985:
1982:
1978:
1975:
1974:
1973:
1970:
1968:
1965:
1963:
1960:
1958:
1955:
1953:
1950:
1946:
1943:
1942:
1941:
1938:
1934:
1931:
1930:
1929:
1926:
1924:
1921:
1919:
1916:
1914:
1910:
1906:
1902:
1899:
1895:
1892:
1890:
1887:
1885:
1882:
1881:
1880:
1877:
1876:
1874:
1872:
1868:
1864:
1858:
1855:
1853:
1850:
1848:
1845:
1844:
1842:
1840:
1836:
1832:
1826:
1823:
1821:
1818:
1817:
1812:
1809:
1807:
1804:
1802:
1799:
1798:
1797:
1796:Phospholipase
1794:
1793:
1788:
1785:
1783:
1780:
1778:
1775:
1773:
1770:
1768:
1765:
1763:
1760:
1758:
1755:
1753:
1750:
1748:
1744:
1741:
1739:
1736:
1735:
1734:
1731:
1730:
1727:
1724:
1722:
1719:
1717:
1714:
1710:
1707:
1705:
1702:
1701:
1700:
1697:
1696:
1694:
1690:
1686:
1682:
1677:
1673:
1669:
1662:
1657:
1655:
1650:
1648:
1643:
1642:
1639:
1628:
1623:
1619:
1615:
1611:
1604:
1601:
1596:
1592:
1587:
1582:
1577:
1572:
1568:
1564:
1560:
1553:
1550:
1545:
1541:
1536:
1531:
1527:
1523:
1519:
1512:
1509:
1504:
1500:
1495:
1490:
1485:
1480:
1476:
1472:
1468:
1461:
1458:
1453:
1449:
1445:
1441:
1437:
1433:
1429:
1425:
1418:
1415:
1410:
1406:
1402:
1398:
1395:(8): 553–68.
1394:
1390:
1389:Life Sciences
1383:
1380:
1375:
1371:
1366:
1361:
1357:
1353:
1349:
1342:
1340:
1338:
1336:
1334:
1332:
1330:
1326:
1316:
1310:
1307:
1302:
1298:
1294:
1290:
1287:(3): 533–46.
1286:
1282:
1274:
1272:
1270:
1268:
1264:
1259:
1255:
1251:
1247:
1242:
1237:
1233:
1229:
1225:
1221:
1217:
1210:
1208:
1206:
1204:
1202:
1200:
1196:
1191:
1187:
1183:
1179:
1176:(3): 366–98.
1175:
1171:
1164:
1162:
1160:
1158:
1154:
1149:
1145:
1141:
1137:
1133:
1129:
1125:
1121:
1114:
1112:
1110:
1108:
1106:
1104:
1102:
1100:
1098:
1096:
1094:
1092:
1088:
1082:
1078:
1075:
1074:
1070:
1068:
1066:
1062:
1054:
1052:
1046:
1044:
1043:intolerance.
1042:
1038:
1034:
1030:
1026:
1021:
1019:
1015:
1010:
1008:
1004:
1000:
992:
989:
985:
983:
979:
976:
972:
969:
965:
964:
963:
961:
954:
949:
947:
935:
932:
928:
925:
921:
920:
919:
917:
909:
907:
901:
898:
897:
896:
892:
890:
885:
883:
878:
876:
870:
868:
860:
857:
845:
841:
837:
829:
827:
823:
821:
817:
809:
806:
803:
800:
799:
798:
796:
788:
786:Linker region
785:
782:
781:
780:
778:
773:
771:
767:
763:
758:
756:
752:
748:
744:
740:
736:
728:
726:
724:
720:
715:
713:
709:
705:
701:
698:
694:
690:
686:
683:
679:
675:
671:
667:
663:
659:
655:
651:
647:
639:
637:
634:
632:
628:
623:
621:
617:
613:
609:
599:
592:
588:
584:
582:
579:
575:
571:
569:
566:
565:
562:
557:
556:T-lymphocytes
552:
549:- Developing
547:
542:
537:
532:
527:
523:
521:
516:
511:
505:
499:
495:
493:
490:
489:
485:
482:
480:
479:
476:
470:
468:
466:
462:
454:
451:
448:
447:
446:
442:
440:
436:
432:
429:usage of the
428:
424:
420:
416:
412:
407:
405:
401:
396:
383:
380:
376:
373:
370:
366:
361:
357:
354:
353:
349:
346:
344:
340:
335:
332:
329:
327:
323:
320:
317:
315:
311:
308:
305:
303:
299:
296:
293:
291:
287:
284:
281:
279:
275:
271:
267:
262:
258:
254:
243:
240:
236:
233:
230:
226:
221:
217:
214:
213:
209:
206:
204:
200:
195:
192:
189:
187:
183:
180:
177:
175:
171:
168:
165:
163:
159:
156:
153:
151:
147:
144:
141:
139:
135:
131:
127:
122:
118:
114:
108:
106:
104:
98:
96:
92:
88:
84:
81:
77:
76:heart failure
73:
69:
65:
57:
55:
53:
49:
45:
41:
37:
36:gene families
33:
29:
21:
2749:Translocases
2746:
2733:
2720:
2707:
2694:
2684:Transferases
2681:
2668:
2525:Binding site
2306:}}
2300:{{
2264:Endonuclease
2195:ribonuclease
2135:
2084:
1918:Nucleotidase
1839:Thioesterase
1617:
1613:
1603:
1566:
1563:ERJ Open Res
1562:
1552:
1525:
1522:Br J Anaesth
1521:
1511:
1474:
1470:
1460:
1427:
1423:
1417:
1392:
1388:
1382:
1355:
1351:
1309:
1284:
1280:
1223:
1219:
1173:
1169:
1123:
1119:
1058:
1050:
1022:
1011:
1006:
1002:
996:
958:
913:
905:
893:
886:
879:
874:
871:
869:hydrolysis.
833:
824:
813:
792:
774:
759:
732:
716:
643:
635:
624:
605:
595:
577:
576:-associated
567:
491:
474:
458:
443:
434:
430:
422:
418:
414:
408:
392:
350:
256:
210:
116:
99:
83:side-effects
61:
27:
26:
2520:Active site
2439:Nuclease S1
2210:Exonuclease
2104:Lecithinase
1933:Calcineurin
1871:Phosphatase
1777:Lipoprotein
1767:Endothelial
1620:(1): 12–7.
1471:JCI Insight
1315:WO 03012030
1001:maturation
970:aggregation
966:antagonize
910:Active site
891:mechanism.
795:hydrophobic
633:fractions.
561:Macrophages
536:Hepatocytes
372:Swiss-model
264:Identifiers
232:Swiss-model
124:Identifiers
95:intravenous
2792:Categories
2723:Isomerases
2697:Hydrolases
2564:Regulation
1752:Pancreatic
1689:Carboxylic
1083:References
1014:Cilostazol
990:relaxation
977:maturation
955:Inhibitors
859:hydrolysis
747:hydrolysis
743:amino acid
739:C-terminus
737:, and the
735:N-terminus
689:adipocytes
658:Hydrolysis
648:pathways.
640:Regulation
631:microsomal
622:envelope.
531:Adipocytes
433:gene. The
427:startcodon
368:Structures
363:Search for
337:Other data
228:Structures
223:Search for
197:Other data
87:indication
80:arrhythmic
2602:EC number
2329:RNase III
2187:(includes
2128:Sulfatase
2041:Autotaxin
1905:Prostatic
1757:Lysosomal
1672:esterases
1668:Hydrolase
882:substrate
770:inhibitor
766:selective
729:Structure
712:lipolysis
581:cytosolic
510:Platelets
465:cytosolic
452:only NHR2
319:NM_000922
278:NCBI gene
179:NM_000921
138:NCBI gene
91:milrinone
72:Molecules
48:effectors
2808:EC 3.1.4
2626:Kinetics
2550:Cofactor
2513:Activity
2423:RNase T1
2185:Nuclease
1820:Cutinase
1595:32280667
1544:24638233
1503:29367458
1452:19506507
1444:29107068
1301:12920188
1250:15798894
1241:11139162
1190:16102838
1140:16968949
1071:See also
1003:in vitro
986:enhance
968:platelet
931:arginine
816:divalent
587:Membrane
574:Membrane
382:InterPro
242:InterPro
58:Function
2782:Biology
2736:Ligases
2506:Enzymes
2396:RNase E
2391:RNase Z
2386:RNase A
2381:RNase P
2354:RNase H
1972:Phytase
1772:Hepatic
1747:Lingual
1743:Gastric
1586:7132035
1494:5821178
1409:1650876
1374:9102399
1258:9806864
1148:7397281
1041:glucose
1037:β-cells
1025:insulin
1007:in vivo
924:adenine
836:enzymes
700:residue
685:tissues
678:adipose
674:insulin
620:nucleus
546:β cells
461:soluble
439:isoform
395:mammals
378:Domains
348:Chr. 11
326:UniProt
238:Domains
208:Chr. 12
186:UniProt
103:hypoxia
64:cardiac
2768:Portal
2710:Lyases
2334:Drosha
2259:3.1.21
2227:RecBCD
2205:3.1.11
1825:PETase
1733:Lipase
1593:
1583:
1542:
1501:
1491:
1450:
1442:
1407:
1372:
1321:
1299:
1256:
1248:
1238:
1188:
1146:
1138:
1055:Asthma
1047:Cancer
1033:leptin
1031:, and
999:oocyte
975:oocyte
973:block
846:with K
762:potent
723:enzyme
708:lipase
704:kinase
697:serine
618:, and
541:Kidney
520:Kidney
515:Oocyte
486:PDE3B
483:PDE3A
467:form.
441:only.
331:Q13370
314:RefSeq
307:602047
269:Symbol
191:Q14432
174:RefSeq
167:123805
129:Symbol
97:form.
50:, and
2662:Types
2343:Dicer
2298:;see
2124:3.1.6
2094:PDE4B
2090:PDE4A
2028:3.1.4
1997:IMPA3
1993:IMPA2
1989:IMPA1
1867:3.1.3
1835:3.1.2
1685:3.1.1
1477:(2).
1448:S2CID
1254:S2CID
1144:S2CID
982:heart
768:PDE3
682:liver
616:golgi
551:sperm
498:Heart
435:PDE3B
431:PDE3A
423:PDE3A
419:PDE3B
415:PDE3A
411:genes
352:p15.2
343:Locus
272:PDE3B
203:Locus
132:PDE3A
30:is a
2754:list
2747:EC7
2741:list
2734:EC6
2728:list
2721:EC5
2715:list
2708:EC4
2702:list
2695:EC3
2689:list
2682:EC2
2676:list
2669:EC1
2261:-31:
2207:-16:
2193:and
2099:PDE5
2085:PDE3
2080:PDE2
2075:PDE1
1967:PTEN
1952:OCRL
1945:PP2A
1894:ALPP
1889:ALPL
1884:ALPI
1678:3.1)
1591:PMID
1540:PMID
1499:PMID
1440:PMID
1405:PMID
1370:PMID
1297:PMID
1246:PMID
1186:PMID
1136:PMID
1029:IGF1
1005:and
916:cAMP
867:cGMP
865:for
856:cAMP
854:for
844:cAMP
842:and
840:cGMP
820:ions
775:The
764:and
755:cGMP
753:and
751:cAMP
719:drug
680:and
670:cGMP
666:cGMP
662:cAMP
652:and
629:and
417:and
402:and
302:OMIM
295:8779
290:HGNC
283:5140
162:OMIM
155:8778
150:HGNC
143:5139
66:and
28:PDE3
2416:4/5
1622:doi
1581:PMC
1571:doi
1530:doi
1526:112
1489:PMC
1479:doi
1432:doi
1428:361
1397:doi
1360:doi
1356:272
1289:doi
1236:PMC
1228:doi
1178:doi
1174:109
1128:doi
863:max
852:max
749:of
695:of
676:in
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