Abstract
Structurally diverse carbazole alkaloids are valuable due to their pharmaceutical properties and have been isolated from nature. Experimental knowledge on carbazole biosynthesis is limited. The latest development of in silico analysis of the biosynthetic gene clusters for bacterial carbazoles has allowed studies on the biosynthesis of a carbazole skeleton, which was established by sequential enzyme-coupling reactions associated with an unprecedented carbazole synthase, a thiamine-dependent enzyme, and a ketosynthase-like enzyme. This review describes the carbazole biosynthetic mechanism, which includes a key step in enzymatic formation of a tricyclic carbazole skeleton, followed by modifications such as prenylation and hydroxylation in the skeleton.
Highlights
Carbazole, a tricycle consisting of two benzene rings fused on either side of a pyrrole core, was first isolated from coal tar in 1872 [1]
Heterocyclic molecules with a carbazole system possess an indole-like structure with a benzene ring fused onto the 2,3-positions of an indole ring, and a large π-conjugated backbone that can afford chemical features such as electrophilic aromatic substitution, oxidative reactions, and alkylation reactions, which generate a variety of modified derivatives concomitant with biological activities [2]
Biochemical studies on Carquinostatins A (CQS) biosynthesis clearly established that precarquinostatin is synthesized from α-hydroxy-β-keto acid through sequential alkylation and cyclization reactions catalyzed by CqsB1 and CqsB2, respectively
Summary
A tricycle consisting of two benzene rings fused on either side of a pyrrole core, was first isolated from coal tar in 1872 [1]. Heterocyclic molecules with a carbazole system possess an indole-like structure with a benzene ring fused onto the 2,3-positions of an indole ring, and a large π-conjugated backbone that can afford chemical features such as electrophilic aromatic substitution, oxidative reactions, and alkylation reactions, which generate a variety of modified derivatives concomitant with biological activities [2] These compounds have been isolated from various organisms, including higher plants, fungi, and some bacteria [1]. Biochemical studies on CQS biosynthesis clearly established that precarquinostatin is synthesized from α-hydroxy-β-keto acid through sequential alkylation and cyclization reactions catalyzed by CqsB1 and CqsB2, respectively. CqsB1 and NzsJ are the first identified KASIII-like enzymes that catalyze the condensation of a β-hydroxy acyl side chain and an indole-containing derivative in carbazole alkaloid biosynthesis. AAcccceessssiioonn nnuummbbeerrss:: CCqqssBB11 ((BBFF2244992233..11)) iinn rreedd,, CCqqssBB55 ((BBBBFF2244992277..11)) iinn rreedd,, NNpphhTT77(D(7DU7RUVR0V.10).,1C),erJC(AerEJ I9(1A06E9I.911),0C69h.1lB), (ACAhlZB76767(A9.A1)Z, P77tm67R9.(1A),CJ2P4tm87R6.1)(,AMCxJn2B48(7A6G.1S),772M82x.n1)B, P(AqsGDS7(P7228025.812).,2P),qEsDcK(AP2S0I5II8(2P.20)A, E6cRK0A.1S),IIFIa(bPH0A(A6RA0Q.10),8F9a2b9H.1,(AAAACQ1088190249..11,, CAAAMC1588180045..11,,CAACMI8588888035.1.1,, QA5C4I280868.813, .Q1,9FQ6D5442.106, .P17, 23Q992F.16,DA4A.1V, 8P4077273.912,.1W, PA_0A1V238842007878.1.1, , WWPP__000132936892307878..11,, WWPP__000033997699733757.1.1),, FWabPB_0(Y03P9_7090713858.111),4F5.a1b,BN(PY_P4_1060812868.11,1Z4P5._10,4N56P2_843176.18,2Z6.P1_, 0Z0P1_3044959622.28,3A7.A1,AZ9P9_404091.13)4, 9F9a2b.F2,(ANAP_A69495464893..11),, NFaPb_F34(N49P4_56.14,56Y8P3_.11,4N36P7_93.414, 9N45P.1_,4Y15P6_1134.316, 7W9.1P,_N01P1_042185362133..11,, WYPP__104131607298.312)3; .1ty, YpeP_I14P3K67S9.[1A);mtyppheAI (PAKASK[7A3m51p2h.1A), (AAvAeKA713(5B1A2.C1)6,8A64v8e.A1), O(BlAmCA6186(B4A8.1C)7, 0O6l1m0.A1), P(BikAACI7(0Q691Z0.G1)I,5P.1i)k,ARIev(QA9(ZBGAIK5.614),6R49e.v1A), L(BsdA1K16(4B6A4G9.815),02L6.s1d),1M1 o(nBAAIG(A85N02Z65.214),59M.1)o, n8A,8aI -d(eAoNxyZo5l2e4a5n9d.o1l)i,de8,s8yan-dtheaosxey1ol(eAaAndF8o2li4d0e8.1s:1y0n6th2–a1s4e741, A(AAAFF8822440088.1.1:2:1504682-2–917417)4],; AitAerFa8t2iv4e08t.y1:p2e54I8-P29K7S1)][;Aiztie2r6ati(vAeBYty8p3e16I4.P1K),SP[cAtSzi2(B6A(FA9B2Y60813.116)4, .1P)o, kPMct1S ((ABCANF9624680311.1.1)),,PAovkiMM1(X(A5C57N7664.18)3, 1C.1h)l,BA1v(iAMA(ZX7575677736..11))],; CenhelBd1iy(nAeAtyZp7e76I7P3.K1)S];[eAneerdEiy(AneAtOyp25e8I64P.K1)S, E[AspeErE((AAAAPO9225184684.1.1)),, EPskpsEE ((AAAAPO9225194084.1.1),),PkSsgEcE(A(AAON2Y5990444.710).,1S)g];cEK(SAαN[YA9c4t4I7O0R.1F)1]; K(NSαP_[6A2c9t2IO37R.1F), E(NncPA_6(2A9A23F78.11)7,28E.1n)c,AOx(yAAA(FA8A17Z2788.13).O1)x,yGArhA(A(AAZA7M8332356.15)3,.1G)]r; hKASβ([A(TAcMmL33(6A5A3.1A)6];75K1S6β.1),[(STncoma2L ((CAAAAA1627051186..11)),, AScntIoOaR2F2(C(CAAAA124051084.41.)1,), AAcktnIOCR(FA2AF(C70A1A074.510),44S.i1m),A2A(kAnACK0(6A7A85F.710)]1;0t7y.1p)e, IISIimPKAS2 [(RApApKA06(W78P5_.10)1];102ty7p65e3.1I)I,IRpPpKAS (W[RPp_p01A238(2W07P7_.011),1R02p7p6A53(.1W),P_R00p3p9A709(3W7.1P)_,0R1p23p8A20(7E7F.D1)7, 07R2p0.p1A), R(WppPA_0(0W39P7_00973875.12)4,27R2p.1p),AGc(sE(FNDP7_06732102.17)7,.1R),pCpUARS(1W(CP_00S7V8Z562.412)7, 2S.r1s)A, (GBcAsG1(N73P0_16.13)1]2;7K7S.1Q), [CChUmRGSI1 ((ACA0SSV79Z465.91.)1, ),SCrhsAlA1((BAAAGZ1777360913.1.1)]);, CKonSQA (A[CAhZm94G3I86(.1A)A, GSf7s9A45(9B.A1)J,16C46h7lA.21), H(AlsAAZ(B7A76F9032.19)2,1.1C)]o.nA (AAZ94386.1), GfsA (BAJ16467.2), HlsA (BAF02921.1)]
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