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| propionyl-CoA |
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| CHEBI:15539 |
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| An acyl-CoA that results from the formal condensation of the thiol group of coenzyme A with the carboxy group of propionic acid. |
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This entity has been manually annotated by the ChEBI Team.
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CHEBI:8479, CHEBI:14904, CHEBI:14907, CHEBI:26295
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| ZINC000008551120 |
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Molfile
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SDF
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more structures >>
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language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__402405073479655__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol 1VU - Ideal conformer Mrv1927 06092111163D starting HoverWatcher_5 Time for openFile(1VU - Ideal conformer Mrv1927 06092111163D 92 94 0 0 0 0 999 V2000 8.2000 2.2700 -0.9690 O 0 0 0 0 0 0 0 0 0 0 0 0 8.7800 1.2430 -0.0740 P 0 0 1 0 0 5 0 0 0 0 0 0 9.7750 0.2980 -0.9150 O 0 0 0 0 0 0 0 0 0 0 0 0 9.5980 1.9640 1.1110 O 0 0 0 0 0 0 0 0 0 0 0 0 7.5970 0.3510 0.5570 O 0 0 0 0 0 0 0 0 0 0 0 0 6.6280 -0.3310 -0.2410 C 0 0 1 0 0 0 0 0 0 0 0 0 6.6620 -1.8490 0.0460 C 0 0 1 0 0 0 0 0 0 0 0 0 7.6540 -2.1500 1.0300 O 0 0 0 0 0 0 0 0 0 0 0 0 5.2500 -2.1610 0.5890 C 0 0 2 0 0 0 0 0 0 0 0 0 4.7970 -3.4690 0.1110 N 0 0 0 0 0 0 0 0 0 0 0 0 5.0750 -4.6840 0.6850 C 0 0 0 0 0 0 0 0 0 0 0 0 5.7660 -5.0830 1.7480 N 0 0 0 0 0 0 0 0 0 0 0 0 5.8520 -6.3610 2.0510 C 0 0 0 0 0 0 0 0 0 0 0 0 5.2680 -7.3010 1.3300 N 0 0 0 0 0 0 0 0 0 0 0 0 4.5560 -6.9980 0.2500 C 0 0 0 0 0 0 0 0 0 0 0 0 3.9470 -7.9900 -0.4990 N 0 0 0 0 0 0 0 0 0 0 0 0 4.4350 -5.6460 -0.1140 C 0 0 0 0 0 0 0 0 0 0 0 0 3.8100 -4.9810 -1.1160 N 0 0 0 0 0 0 0 0 0 0 0 0 4.0170 -3.7030 -0.9830 C 0 0 0 0 0 0 0 0 0 0 0 0 4.4110 -1.1110 0.0580 O 0 0 0 0 0 0 0 0 0 0 0 0 5.1990 0.0950 0.1620 C 0 0 2 0 0 0 0 0 0 0 0 0 4.6690 1.1610 -0.7990 C 0 0 1 0 0 0 0 0 0 0 0 0 3.3970 1.6240 -0.3430 O 0 0 0 0 0 0 0 0 0 0 0 0 2.5460 2.7520 -1.1150 P 0 0 1 0 0 5 0 0 0 0 0 0 3.3450 4.1490 -1.0750 O 0 0 0 0 0 0 0 0 0 0 0 0 2.3430 2.3400 -2.5220 O 0 0 0 0 0 0 0 0 0 0 0 0 1.1160 2.9310 -0.3970 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.2990 3.5430 -0.8600 P 0 0 1 0 0 5 0 0 0 0 0 0 -0.0690 4.7650 -1.6630 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.0880 2.4570 -1.7500 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.1760 3.9110 0.4390 O 0 0 0 0 0 0 0 0 0 0 0 0 -2.4410 4.5700 0.3630 C 0 0 1 0 0 0 0 0 0 0 0 0 -3.0000 4.7660 1.7730 C 0 0 1 0 0 0 0 0 0 0 0 0 -3.1740 3.4040 2.4480 C 0 0 0 0 0 0 0 0 0 0 0 0 -2.0290 5.6200 2.5920 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.3550 5.4710 1.6920 C 0 0 1 0 0 0 0 0 0 0 0 0 -4.1740 6.7940 1.1820 O 0 0 0 0 0 0 0 0 0 0 0 0 -5.2680 4.7000 0.7740 C 0 0 0 0 0 0 0 0 0 0 0 0 -5.5950 5.1740 -0.2940 O 0 0 0 0 0 0 0 0 0 0 0 0 -5.7210 3.4850 1.1390 N 0 0 0 0 0 0 0 0 0 0 0 0 -6.5290 2.6940 0.2080 C 0 0 1 0 0 0 0 0 0 0 0 0 -6.9110 1.3660 0.8650 C 0 0 1 0 0 0 0 0 0 0 0 0 -7.7420 0.5520 -0.0940 C 0 0 0 0 0 0 0 0 0 0 0 0 -8.0030 0.9900 -1.1940 O 0 0 0 0 0 0 0 0 0 0 0 0 -8.1950 -0.6640 0.2720 N 0 0 0 0 0 0 0 0 0 0 0 0 -9.0020 -1.4550 -0.6600 C 0 0 1 0 0 0 0 0 0 0 0 0 -9.3840 -2.7830 -0.0030 C 0 0 1 0 0 0 0 0 0 0 0 0 -10.3820 -3.7610 -1.1540 S 0 0 0 0 0 0 0 0 0 0 0 0 -10.6640 -5.1510 -0.1960 C 0 0 0 0 0 0 0 0 0 0 0 0 -10.2060 -5.2180 0.9260 O 0 0 0 0 0 0 0 0 0 0 0 0 -11.4810 -6.2920 -0.7460 C 0 0 1 0 0 0 0 0 0 0 0 0 -11.5800 -7.4010 0.3040 C 0 0 0 0 0 0 0 0 0 0 0 0 10.1920 -0.3990 -0.3910 H 0 0 0 0 0 0 0 0 0 0 0 0 10.3280 2.5200 0.8040 H 0 0 0 0 0 0 0 0 0 0 0 0 6.7990 -0.1390 -1.3000 H 0 0 0 0 0 0 0 0 0 0 0 0 6.8530 -2.4070 -0.8710 H 0 0 0 0 0 0 0 0 0 0 0 0 7.7190 -3.0900 1.2480 H 0 0 0 0 0 0 0 0 0 0 0 0 5.2470 -2.1340 1.6780 H 0 0 0 0 0 0 0 0 0 0 0 0 6.4220 -6.6520 2.9210 H 0 0 0 0 0 0 0 0 0 0 0 0 4.0380 -8.9200 -0.2370 H 0 0 0 0 0 0 0 0 0 0 0 0 3.4300 -7.7560 -1.2850 H 0 0 0 0 0 0 0 0 0 0 0 0 3.6340 -2.9410 -1.6450 H 0 0 0 0 0 0 0 0 0 0 0 0 5.1880 0.4670 1.1860 H 0 0 0 0 0 0 0 0 0 0 0 0 5.3690 1.9960 -0.8360 H 0 0 0 0 0 0 0 0 0 0 0 0 4.5640 0.7320 -1.7960 H 0 0 0 0 0 0 0 0 0 0 0 0 3.5140 4.4800 -0.1820 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.2730 1.6290 -1.2870 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.3180 5.5400 -0.1170 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.1330 3.9610 -0.2200 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.1960 2.9500 2.6080 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.6750 3.5340 3.4070 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.7740 2.7560 1.8090 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.9680 6.6180 2.1580 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.3860 5.6920 3.6190 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.0420 5.1580 2.5820 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.7990 5.5230 2.6860 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.7830 6.8250 0.2990 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.5130 3.1340 2.0190 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.4330 3.2460 -0.0480 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.9530 2.4990 -0.6970 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.0070 0.8140 1.1210 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.4860 1.5600 1.7700 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.9860 -1.0150 1.1520 H 0 0 0 0 0 0 0 0 0 0 0 0 -9.9070 -0.9030 -0.9160 H 0 0 0 0 0 0 0 0 0 0 0 0 -8.4270 -1.6500 -1.5650 H 0 0 0 0 0 0 0 0 0 0 0 0 -8.4800 -3.3350 0.2540 H 0 0 0 0 0 0 0 0 0 0 0 0 -9.9600 -2.5890 0.9020 H 0 0 0 0 0 0 0 0 0 0 0 0 -12.4810 -5.9370 -0.9940 H 0 0 0 0 0 0 0 0 0 0 0 0 -11.0010 -6.6830 -1.6430 H 0 0 0 0 0 0 0 0 0 0 0 0 -12.1700 -8.2260 -0.0940 H 0 0 0 0 0 0 0 0 0 0 0 0 -10.5800 -7.7560 0.5530 H 0 0 0 0 0 0 0 0 0 0 0 0 -12.0600 -7.0100 1.2010 H 0 0 0 0 0 0 0 0 0 0 0 0 29 28 2 0 0 0 0 52 51 1 0 0 0 0 26 24 2 0 0 0 0 32 31 1 0 0 0 0 32 33 1 0 0 0 0 35 33 1 0 0 0 0 28 31 1 1 0 0 0 28 30 1 0 0 0 0 28 27 1 0 0 0 0 34 33 1 0 0 0 0 51 49 1 0 0 0 0 33 36 1 0 0 0 0 24 27 1 1 0 0 0 24 25 1 0 0 0 0 24 23 1 0 0 0 0 49 48 1 0 0 0 0 49 50 2 0 0 0 0 48 47 1 0 0 0 0 36 37 1 0 0 0 0 36 38 1 0 0 0 0 23 22 1 0 0 0 0 39 38 2 0 0 0 0 38 40 1 0 0 0 0 45 46 1 0 0 0 0 45 43 1 0 0 0 0 22 21 1 0 0 0 0 42 43 1 0 0 0 0 42 41 1 0 0 0 0 40 41 1 0 0 0 0 46 47 1 0 0 0 0 43 44 2 0 0 0 0 6 7 1 0 0 0 0 6 21 1 0 0 0 0 6 5 1 0 0 0 0 19 18 2 0 0 0 0 19 10 1 0 0 0 0 7 8 1 0 0 0 0 7 9 1 0 0 0 0 21 20 1 0 0 0 0 18 17 1 0 0 0 0 1 2 2 0 0 0 0 3 2 1 0 0 0 0 20 9 1 0 0 0 0 5 2 1 0 0 0 0 10 9 1 0 0 0 0 10 11 1 0 0 0 0 2 4 1 0 0 0 0 17 11 1 0 0 0 0 17 15 2 0 0 0 0 11 12 2 0 0 0 0 16 15 1 0 0 0 0 15 14 1 0 0 0 0 12 13 1 0 0 0 0 14 13 2 0 0 0 0 3 53 1 0 0 0 0 4 54 1 0 0 0 0 6 55 1 6 0 0 0 7 56 1 6 0 0 0 8 57 1 0 0 0 0 9 58 1 1 0 0 0 13 59 1 0 0 0 0 16 60 1 0 0 0 0 16 61 1 0 0 0 0 19 62 1 0 0 0 0 21 63 1 1 0 0 0 22 64 1 0 0 0 0 22 65 1 0 0 0 0 25 66 1 0 0 0 0 30 67 1 0 0 0 0 32 68 1 0 0 0 0 32 69 1 0 0 0 0 34 70 1 0 0 0 0 34 71 1 0 0 0 0 34 72 1 0 0 0 0 35 73 1 0 0 0 0 35 74 1 0 0 0 0 35 75 1 0 0 0 0 36 76 1 1 0 0 0 37 77 1 0 0 0 0 40 78 1 0 0 0 0 41 79 1 0 0 0 0 41 80 1 0 0 0 0 42 81 1 0 0 0 0 42 82 1 0 0 0 0 45 83 1 0 0 0 0 46 84 1 0 0 0 0 46 85 1 0 0 0 0 47 86 1 0 0 0 0 47 87 1 0 0 0 0 51 88 1 0 0 0 0 51 89 1 0 0 0 0 52 90 1 0 0 0 0 52 91 1 0 0 0 0 52 92 1 0 0 0 0 M END): 19 ms reading 92 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. Use getProperty "modelInfo" or getProperty "auxiliaryInfo" to inspect them. Default Van der Waals type for model set to Babel 92 atoms created ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation Script completed Jmol script terminated
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| Propionyl-CoA is a coenzyme A derivative of propionic acid. It is composed of a 24 total carbon chain (without the coenzyme, it is a 3 carbon structure) and its production and metabolic fate depend on which organism it is present in. Several different pathways can lead to its production, such as through the catabolism of specific amino acids or the oxidation of odd-chain fatty acids. It later can be broken down by propionyl-CoA carboxylase or through the methylcitrate cycle. In different organisms, however, propionyl-CoA can be sequestered into controlled regions, to alleviate its potential toxicity through accumulation. Genetic deficiencies regarding the production and breakdown of propionyl-CoA also have great clinical and human significance. |
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Read full article at Wikipedia
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InChI=1S/C24H40N7O17P3S/c1- 4-15(33)52-8-7-26-14(32)5-6-27-22(36)19(35)24(2,3)10-45-51(42,43)48-50(40,41)44-9-13-18(47-49(37,38)39)17(34)23(46-13)31-12-30-16-20(25)28-11-29-21(16)31/h11-13,17-19,23,34-35H,4-10H2,1-3H3,(H,26,32)(H,27,36)(H,40,41)(H,42,43)(H2,25,28,29)(H2,37,38,39)/t13-,17-,18-,19+,23-/m1/s1 |
| QAQREVBBADEHPA-IEXPHMLFSA-N |
| CCC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1OP(O)(O)=O)N1C=NC2=C1N=CN=C2N |
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Escherichia coli
(NCBI:txid562)
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See:
PubMed
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acyl donor
Any donor that can transfer acyl groups between molecular entities.
(via acyl-CoA )
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Escherichia coli metabolite
Any bacterial metabolite produced during a metabolic reaction in Escherichia coli.
metabolite
Any intermediate or product resulting from metabolism. The term 'metabolite' subsumes the classes commonly known as primary and secondary metabolites.
mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
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View more via ChEBI Ontology
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3'-phosphoadenosine 5'-(3-{(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-[(3-oxo-3-{[2-(propanoylsulfanyl)ethyl]amino}propyl)amino]butyl} dihydrogen diphosphate)
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Propanoyl-CoA
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KEGG COMPOUND
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propanoyl-coenzyme A
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ChEBI
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Propionyl coenzyme A
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KEGG COMPOUND
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Propionyl-CoA
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KEGG COMPOUND
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Propionyl-coenzyme A
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ChemIDplus
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S-propanoyl-CoA
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ChEBI
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S-propanoyl-coenzyme A
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ChEBI
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S-Propionyl-coenzym-A
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ChEBI
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S-Propionylcoenzyme A
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ChemIDplus
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317-66-8
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CAS Registry Number
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KEGG COMPOUND
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317-66-8
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CAS Registry Number
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ChemIDplus
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78167
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Reaxys Registry Number
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Reaxys
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Blaisse MR, Fu B, Chang MCY (2018)
Structural and Biochemical Studies of Substrate Selectivity in Ascaris suum Thiolases.
Biochemistry 57, 3155-3166 [PubMed:29381332]
[show Abstract]
Thiolases are a class of carbon-carbon bond forming enzymes with important applications in biotechnology and metabolic engineering as they provide a general method for the condensation of two acyl coenzyme A (CoA) substrates. As such, developing a greater understanding of their substrate selectivity would expand our ability to engineer the enzymatic or microbial production of a broad range of small-molecule targets. Here, we report the crystal structures and biochemical characterization of Acat2 and Acat5, two biosynthetic thiolases from Ascaris suum with varying selectivity toward branched compared to linear compounds. The structure of the Acat2-C91S mutant bound to propionyl-CoA shows that the terminal methyl group of the substrate, representing the α-branch point, is directed toward the conserved Phe 288 and Met 158 residues. In Acat5, the Phe ring is rotated to accommodate a hydroxyl-π interaction with an adjacent Thr side chain, decreasing space in the binding pocket and possibly accounting for its strong preference for linear substrates compared to Acat2. Comparison of the different Acat thiolase structures shows that Met 158 is flexible, adopting alternate conformations with the side chain rotated toward or away from a covering loop at the back of the active site. Mutagenesis of residues in the covering loop in Acat5 with the corresponding residues from Acat2 allows for highly increased accommodation of branched substrates, whereas the converse mutations do not significantly affect Acat2 substrate selectivity. Our results suggest an important contribution of second-shell residues to thiolase substrate selectivity and offer insights into engineering this enzyme class. | Shen H, Campanello GC, Flicker D, Grabarek Z, Hu J, Luo C, Banerjee R, Mootha VK (2017)
The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12.
Cell 171, 771-782.e11 [PubMed:29056341]
[show Abstract]
CLYBL encodes a ubiquitously expressed mitochondrial enzyme, conserved across all vertebrates, whose cellular activity and pathway assignment are unknown. Its homozygous loss is tolerated in seemingly healthy individuals, with reduced circulating B12 levels being the only and consistent phenotype reported to date. Here, by combining enzymology, structural biology, and activity-based metabolomics, we report that CLYBL operates as a citramalyl-CoA lyase in mammalian cells. Cells lacking CLYBL accumulate citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that includes itaconate, a recently identified human anti-microbial metabolite and immunomodulator. We report that CLYBL loss leads to a cell-autonomous defect in the mitochondrial B12 metabolism and that itaconyl-CoA is a cofactor-inactivating, substrate-analog inhibitor of the mitochondrial B12-dependent methylmalonyl-CoA mutase (MUT). Our work de-orphans the function of human CLYBL and reveals that a consequence of exposure to the immunomodulatory metabolite itaconate is B12 inactivation. | Srirangan K, Bruder M, Akawi L, Miscevic D, Kilpatrick S, Moo-Young M, Chou CP (2017)
Recent advances in engineering propionyl-CoA metabolism for microbial production of value-added chemicals and biofuels.
Critical reviews in biotechnology 37, 701-722 [PubMed:27557613]
[show Abstract]
Diminishing fossil fuel reserves and mounting environmental concerns associated with petrochemical manufacturing practices have generated significant interests in developing whole-cell biocatalytic systems for the production of value-added chemicals and biofuels. Although acetyl-CoA is a common natural biogenic precursor for the biosynthesis of numerous metabolites, propionyl-CoA is unpopular and non-native to most organisms. Nevertheless, with its C3-acyl moiety as a discrete building block, propionyl-CoA can serve as another key biogenic precursor to several biological products of industrial importance. As a result, engineering propionyl-CoA metabolism, particularly in genetically tractable hosts with the use of inexpensive feedstocks, has paved an avenue for novel biomanufacturing. Herein, we present a systematic review on manipulation of propionyl-CoA metabolism as well as relevant genetic and metabolic engineering strategies for microbial production of value-added chemicals and biofuels, including odd-chain alcohols and organic acids, bio(co)polymers and polyketides. [Formula: see text]. | Xu Z, Wang M, Ye BC (2017)
TetR Family Transcriptional Regulator PccD Negatively Controls Propionyl Coenzyme A Assimilation in Saccharopolyspora erythraea.
Journal of bacteriology 199, e00281-17 [PubMed:28760847]
[show Abstract]
Propanol stimulates erythromycin biosynthesis by increasing the supply of propionyl coenzyme A (propionyl-CoA), a starter unit of erythromycin production in Saccharopolyspora erythraea Propionyl-CoA is assimilated via propionyl-CoA carboxylase to methylmalonyl-CoA, an extender unit of erythromycin. We found that the addition of n-propanol or propionate caused a 4- to 16-fold increase in the transcriptional levels of the SACE_3398-3400 locus encoding propionyl-CoA carboxylase, a key enzyme in propionate metabolism. The regulator PccD was proved to be directly involved in the transcription regulation of the SACE_3398-3400 locus by EMSA and DNase I footprint analysis. The transcriptional levels of SACE_3398-3400 were upregulated 15- to 37-fold in the pccD gene deletion strain (ΔpccD) and downregulated 3-fold in the pccD overexpression strain (WT/pIB-pccD), indicating that PccD was a negative transcriptional regulator of SACE_3398-3400. The ΔpccD strain has a higher growth rate than that of the wild-type strain (WT) on Evans medium with propionate as the sole carbon source, whereas the growth of the WT/pIB-pccD strain was repressed. As a possible metabolite of propionate metabolism, methylmalonic acid was identified as an effector molecule of PccD and repressed its regulatory activity. A higher level of erythromycin in the ΔpccD strain was observed compared with that in the wild-type strain. Our study reveals a regulatory mechanism in propionate metabolism and suggests new possibilities for designing metabolic engineering to increase erythromycin yield.IMPORTANCE Our work has identified the novel regulator PccD that controls the expression of the gene for propionyl-CoA carboxylase, a key enzyme in propionyl-CoA assimilation in S. erythraea PccD represses the generation of methylmalonyl-CoA through carboxylation of propionyl-CoA and reveals an effect on biosynthesis of erythromycin. This finding provides novel insight into propionyl-CoA assimilation, and extends our understanding of the regulatory mechanisms underlying the biosynthesis of erythromycin. | Gotoh K, Nakajima Y, Tajima G, Watanabe Y, Hotta Y, Kataoka T, Kawade Y, Sugiyama N, Ito T, Kimura K, Maeda Y (2017)
Determination of methylmalonyl coenzyme A by ultra high-performance liquid chromatography tandem mass spectrometry for measuring propionyl coenzyme A carboxylase activity in patients with propionic acidemia.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 1046, 195-199 [PubMed:28189105]
[show Abstract]
Propionic acidemia (PA) is an inherited metabolic disease caused by low activity of propionyl coenzyme A (CoA) carboxylase (PCC), which metabolizes propionyl-CoA into methylmalonyl-CoA. Although many patients with PA have been identified by tandem mass spectrometry since the test was first included in neonatal mass screening in the 1990s, the disease severity varies. Thus, determining the specific level of PCC activity is considered to be helpful to grasp the severity of PA. We developed a new PCC assay method by the determination of methylmalonyl-CoA, which is formed by an enzyme reaction using peripheral lymphocytes, based on ultra high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). With methylmalonyl-CoA concentrations of 0.05, 0.5, and 5μmol/L, the intra-assay coefficients of variation (CVs) were 8.2%, 8.7%, and 5.1%, respectively, and the inter-assay CVs were 13.6%, 10.5%, and 5.9%, respectively. The PCC activities of 20 healthy individuals and 6 PA patients were investigated with this assay. Methylmalonyl-CoA was not detected in one PA patient with a severe form of the disease, but the remaining PA patients with mild disease showed residual activities (3.3-7.8%). These results demonstrate that determination of PCC activity with this assay would be useful to distinguish between mild and severe cases of PA to help choose an appropriate treatment plan. | Wongkittichote P, Ah Mew N, Chapman KA (2017)
Propionyl-CoA carboxylase - A review.
Molecular genetics and metabolism 122, 145-152 [PubMed:29033250]
[show Abstract]
Propionyl-CoA carboxylase (PCC) is the enzyme which catalyzes the carboxylation of propionyl-CoA to methylmalonyl-CoA and is encoded by the genes PCCA and PCCB to form a hetero-dodecamer. Dysfunction of PCC leads to the inherited metabolic disorder propionic acidemia, which can result in an affected individual presenting with metabolic acidosis, hyperammonemia, lethargy, vomiting and sometimes coma and death if not treated. Individuals with propionic acidemia also have a number of long term complications resulting from the dysfunction of the PCC enzyme. Here we present an overview of the current knowledge about the structure and function of PCC. We review an updated list of human variants which are published and provide an overview of the disease. | Kaczmarska Z, Ortega E, Goudarzi A, Huang H, Kim S, Márquez JA, Zhao Y, Khochbin S, Panne D (2017)
Structure of p300 in complex with acyl-CoA variants.
Nature chemical biology 13, 21-29 [PubMed:27820805]
[show Abstract]
Histone acetylation plays an important role in transcriptional activation. Histones are also modified by chemically diverse acylations that are frequently deposited by p300, a transcriptional coactivator that uses a number of different acyl-CoA cofactors. Here we report that while p300 is a robust acetylase, its activity gets weaker with increasing acyl-CoA chain length. Crystal structures of p300 in complex with propionyl-, crotonyl-, or butyryl-CoA show that the aliphatic portions of these cofactors are bound in the lysine substrate-binding tunnel in a conformation that is incompatible with substrate transfer. Lysine substrate binding is predicted to remodel the acyl-CoA ligands into a conformation compatible with acyl-chain transfer. This remodeling requires that the aliphatic portion of acyl-CoA be accommodated in a hydrophobic pocket in the enzymes active site. The size of the pocket and its aliphatic nature exclude long-chain and charged acyl-CoA variants, presumably explaining the cofactor preference for p300. | Zarzycki J, Sutter M, Cortina NS, Erb TJ, Kerfeld CA (2017)
In Vitro Characterization and Concerted Function of Three Core Enzymes of a Glycyl Radical Enzyme - Associated Bacterial Microcompartment.
Scientific reports 7, 42757 [PubMed:28202954]
[show Abstract]
Many bacteria encode proteinaceous bacterial microcompartments (BMCs) that encapsulate sequential enzymatic reactions of diverse metabolic pathways. Well-characterized BMCs include carboxysomes for CO2-fixation, and propanediol- and ethanolamine-utilizing microcompartments that contain B12-dependent enzymes. Genes required to form BMCs are typically organized in gene clusters, which promoted their distribution across phyla by horizontal gene transfer. Recently, BMCs associated with glycyl radical enzymes (GREs) were discovered; these are widespread and comprise at least three functionally distinct types. Previously, we predicted one type of these GRE-associated microcompartments (GRMs) represents a B12-independent propanediol-utilizing BMC. Here we functionally and structurally characterize enzymes of the GRM of Rhodopseudomonas palustris BisB18 and demonstrate their concerted function in vitro. The GRM signature enzyme, the GRE, is a dedicated 1,2-propanediol dehydratase with a new type of intramolecular encapsulation peptide. It forms a complex with its activating enzyme and, in conjunction with an aldehyde dehydrogenase, converts 1,2-propanediol to propionyl-CoA. Notably, homologous GRMs are also encoded in pathogenic Escherichia coli strains. Our high-resolution crystal structures of the aldehyde dehydrogenase lead to a revised reaction mechanism. The successful in vitro reconstitution of a part of the GRM metabolism provides insights into the metabolic function and steps in the assembly of this BMC. | Ringel AE, Wolberger C (2016)
Structural basis for acyl-group discrimination by human Gcn5L2.
Acta crystallographica. Section D, Structural biology 72, 841-848 [PubMed:27377381]
[show Abstract]
Gcn5 is a conserved acetyltransferase that regulates transcription by acetylating the N-terminal tails of histones. Motivated by recent studies identifying a chemically diverse array of lysine acyl modifications in vivo, the acyl-chain specificity of the acetyltransferase human Gcn5 (Gcn5L2) was examined. Whereas Gcn5L2 robustly catalyzes lysine acetylation, the acyltransferase activity of Gcn5L2 becomes progressively weaker with increasing acyl-chain length. To understand how Gcn5 discriminates between different acyl-CoA molecules, structures of the catalytic domain of human Gcn5L2 bound to propionyl-CoA and butyryl-CoA were determined. Although the active site of Gcn5L2 can accommodate propionyl-CoA and butyryl-CoA without major structural rearrangements, butyryl-CoA adopts a conformation incompatible with catalysis that obstructs the path of the incoming lysine residue and acts as a competitive inhibitor of Gcn5L2 versus acetyl-CoA. These structures demonstrate how Gcn5L2 discriminates between acyl-chain donors and explain why Gcn5L2 has weak activity for acyl moieties that are larger than an acetyl group. | Luo H, Zhou D, Liu X, Nie Z, Quiroga-Sánchez DL, Chang Y (2016)
Production of 3-Hydroxypropionic Acid via the Propionyl-CoA Pathway Using Recombinant Escherichia coli Strains.
PloS one 11, e0156286 [PubMed:27227837]
[show Abstract]
Our study aimed to produce the commercially promising platform chemical 3-hydroxypropionic acid (3-HP) via the propionyl-CoA pathway in genetically engineered Escherichia coli. Recombinant E. coli Ec-P overexpressing propionyl-CoA dehydrogenase (PACD, encoded by the pacd gene from Candida rugosa) under the T7 promoter produced 1.33 mM of 3-HP in a shake flask culture supplemented with 0.5% propionate. When propionate CoA-transferase (PCT, encoded by the pct gene from Megasphaera elsdenii) and 3-hydroxypropionyl-CoA dehydratase (HPCD, encoded by the hpcd gene from Chloroflexus aurantiacus) were expressed along with PACD, the 3-HP titer of the resulting E. coli Ec-PPH strain was improved by 6-fold. The effect of the cultivation conditions on the 3-HP yield from propionate in the Ec-PPH strain was also investigated. When cultured at 30°C with 1% glucose in addition to propionate, 3-HP production by Ec-PPH increased 2-fold and 12-fold compared to the cultivation at 37°C (4.23 mM) or without glucose (0.68 mM). Deletion of the ygfH gene encoding propionyl-CoA: succinate CoA-transferase from Ec-PPH (resulting in the strain Ec-△Y-PPH) led to increase of 3-HP production in shake flask experiments (15.04 mM), whereas the strain Ec-△Y-PPH with deletion of the prpC gene (encoding methylcitrate synthase in the methylcitrate cycle) produced 17.76 mM of 3-HP. The strain Ec-△Y-△P-PPH with both ygfH and prpC genes deleted produced 24.14 mM of 3-HP, thus showing an 18-fold increase in the 3-HP titer in compare to the strain Ec-P. | Hou J, Xiang H, Han J (2015)
Propionyl coenzyme A (propionyl-CoA) carboxylase in Haloferax mediterranei: Indispensability for propionyl-CoA assimilation and impacts on global metabolism.
Applied and environmental microbiology 81, 794-804 [PubMed:25398867]
[show Abstract]
Propionyl coenzyme A (propionyl-CoA) is an important intermediate during the biosynthesis and catabolism of intracellular carbon storage of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) in haloarchaea. However, the haloarchaeal propionyl-CoA carboxylase (PCC) and its physiological significance remain unclear. In this study, we identified a PCC that catalyzed propionyl-CoA carboxylation with an acetyl-CoA carboxylation side activity in Haloferax mediterranei. Gene knockout/complementation demonstrated that the PCC enzyme consisted of a fusion protein of a biotin carboxylase and a biotin-carboxyl carrier protein (PccA [HFX_2490]), a carboxyltransferase component (PccB [HFX_2478]), and an essential small subunit (PccX [HFX_2479]). Knockout of pccBX led to an inability to utilize propionate and a higher intracellular propionyl-CoA level, indicating that the PCC enzyme is indispensable for propionyl-CoA utilization. Interestingly, H. mediterranei DBX (pccBX-deleted strain) displayed multiple phenotypic changes, including retarded cell growth, decreased glucose consumption, impaired PHBV biosynthesis, and wrinkled cells. A propionyl-CoA concentration equivalent to the concentration that accumulated in DBX cells was demonstrated to inhibit succinyl-CoA synthetase of the tricarboxylic acid cycle in vitro. Genome-wide microarray analysis showed that many genes for glycolysis, pyruvate oxidation, PHBV accumulation, electron transport, and stress responses were affected in DBX. This study not only identified the haloarchaeal PCC for the metabolism of propionyl-CoA, an important intermediate in haloarchaea, but also demonstrated that impaired propionyl-CoA metabolism affected global metabolism in H. mediterranei. | Carter MS, Alber BE (2015)
Transcriptional Regulation by the Short-Chain Fatty Acyl Coenzyme A Regulator (ScfR) PccR Controls Propionyl Coenzyme A Assimilation by Rhodobacter sphaeroides.
Journal of bacteriology 197, 3048-3056 [PubMed:26170412]
[show Abstract]
UnlabelledPropionyl coenzyme A (propionyl-CoA) assimilation by Rhodobacter sphaeroides proceeds via the methylmalonyl-CoA pathway. The activity of the key enzyme of the pathway, propionyl-CoA carboxylase (PCC), was upregulated 20-fold during growth with propionate compared to growth with succinate. Because propionyl-CoA is an intermediate in acetyl-CoA assimilation via the ethylmalonyl-CoA pathway, acetate growth also requires the methylmalonyl-CoA pathway. PCC activities were upregulated 8-fold in extracts of acetate-grown cells compared to extracts of succinate-grown cells. The upregulation of PCC activities during growth with propionate or acetate corresponded to increased expression of the pccB gene, which encodes a subunit of PCC. PccR (RSP_2186) was identified to be a transcriptional regulator required for the upregulation of pccB transcript levels and, consequently, PCC activity: growth substrate-dependent regulation was lost when pccR was inactivated by an in-frame deletion. In the pccR mutant, lacZ expression from a 215-bp plasmid-borne pccB upstream fragment including 27 bp of the pccB coding region was also deregulated. A loss of regulation as a result of mutations in the conserved motifs TTTGCAAA-X4-TTTGCAAA in the presence of PccR allowed the prediction of a possible operator site. PccR, together with homologs from other organisms, formed a distinct clade within the family of short-chain fatty acyl coenzyme A regulators (ScfRs) defined here. Some members from other clades within the ScfR family have previously been shown to be involved in regulating acetyl-CoA assimilation by the glyoxylate bypass (RamB) or propionyl-CoA assimilation by the methylcitrate cycle (MccR).ImportanceShort-chain acyl-CoAs are intermediates in essential biosynthetic and degradative pathways. The regulation of their accumulation is crucial for appropriate cellular function. This work identifies a regulator (PccR) that prevents the accumulation of propionyl-CoA by controlling expression of the gene encoding propionyl-CoA carboxylase, which is responsible for propionyl-CoA consumption by Rhodobacter sphaeroides. Many other Proteobacteria and Actinomycetales contain one or several PccR homologs that group into distinct clades on the basis of the pathway of acyl-CoA metabolism that they control. Furthermore, an upstream analysis of genes encoding PccR homologs allows the prediction of conserved binding motifs for these regulators. Overall, this study evaluates a single regulator of propionyl-CoA assimilation while expanding the knowledge of the regulation of short-chain acyl-CoAs in many bacterial species. | Heine A, Herrmann G, Selmer T, Terwesten F, Buckel W, Reuter K (2014)
High resolution crystal structure of Clostridium propionicum β-alanyl-CoA:ammonia lyase, a new member of the "hot dog fold" protein superfamily.
Proteins 82, 2041-2053 [PubMed:24623648]
[show Abstract]
Clostridium propionicum is the only organism known to ferment β-alanine, a constituent of coenzyme A (CoA) and the phosphopantetheinyl prosthetic group of holo-acyl carrier protein. The first step in the fermentation is a CoA-transfer to β-alanine. Subsequently, the resulting β-alanyl-CoA is deaminated by the enzyme β-alanyl-CoA:ammonia lyase (Acl) to reversibly form ammonia and acrylyl-CoA. We have determined the crystal structure of Acl in its apo-form at a resolution of 0.97 Å as well as in complex with CoA at a resolution of 1.59 Å. The structures reveal that the enyzme belongs to a superfamily of proteins exhibiting a so called "hot dog fold" which is characterized by a five-stranded antiparallel β-sheet with a long α-helix packed against it. The functional unit of all "hot dog fold" proteins is a homodimer containing two equivalent substrate binding sites which are established by the dimer interface. In the case of Acl, three functional dimers combine to a homohexamer strongly resembling the homohexamer formed by YciA-like acyl-CoA thioesterases. Here, we propose an enzymatic mechanism based on the crystal structure of the Acl·CoA complex and molecular docking. | Otzen C, Bardl B, Jacobsen ID, Nett M, Brock M (2014)
Candida albicans utilizes a modified β-oxidation pathway for the degradation of toxic propionyl-CoA.
The Journal of biological chemistry 289, 8151-8169 [PubMed:24497638]
[show Abstract]
Propionyl-CoA arises as a metabolic intermediate from the degradation of propionate, odd-chain fatty acids, and some amino acids. Thus, pathways for catabolism of this intermediate have evolved in all kingdoms of life, preventing the accumulation of toxic propionyl-CoA concentrations. Previous studies have shown that fungi generally use the methyl citrate cycle for propionyl-CoA degradation. Here, we show that this is not the case for the pathogenic fungus Candida albicans despite its ability to use propionate and valerate as carbon sources. Comparative proteome analyses suggested the presence of a modified β-oxidation pathway with the key intermediate 3-hydroxypropionate. Gene deletion analyses confirmed that the enoyl-CoA hydratase/dehydrogenase Fox2p, the putative 3-hydroxypropionyl-CoA hydrolase Ehd3p, the 3-hydroxypropionate dehydrogenase Hpd1p, and the putative malonate semialdehyde dehydrogenase Ald6p essentially contribute to propionyl-CoA degradation and its conversion to acetyl-CoA. The function of Hpd1p was further supported by the detection of accumulating 3-hydroxypropionate in the hpd1 mutant on propionyl-CoA-generating nutrients. Substrate specificity of Hpd1p was determined from recombinant purified enzyme, which revealed a preference for 3-hydroxypropionate, although serine and 3-hydroxyisobutyrate could also serve as substrates. Finally, virulence studies in a murine sepsis model revealed attenuated virulence of the hpd1 mutant, which indicates generation of propionyl-CoA from host-provided nutrients during infection. | Han J, Hou J, Zhang F, Ai G, Li M, Cai S, Liu H, Wang L, Wang Z, Zhang S, Cai L, Zhao D, Zhou J, Xiang H (2013)
Multiple propionyl coenzyme A-supplying pathways for production of the bioplastic poly(3-hydroxybutyrate-co-3-hydroxyvalerate) in Haloferax mediterranei.
Applied and environmental microbiology 79, 2922-2931 [PubMed:23435886]
[show Abstract]
Haloferax mediterranei is able to accumulate the bioplastic poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) with more than 10 mol% 3-hydroxyvalerate (3HV) from unrelated carbon sources. However, the pathways that produce propionyl coenzyme A (propionyl-CoA), an important precursor of 3HV monomer, have not yet been determined. Bioinformatic analysis of H. mediterranei genome indicated that this strain uses multiple pathways for propionyl-CoA biosynthesis, including the citramalate/2-oxobutyrate pathway, the aspartate/2-oxobutyrate pathway, the methylmalonyl-CoA pathway, and a novel 3-hydroxypropionate pathway. Cofeeding of pathway intermediates and inactivating pathway-specific genes supported that these four pathways were indeed involved in the biosynthesis of 3HV monomer. The novel 3-hydroxypropionate pathway that couples CO2 assimilation with PHBV biosynthesis was further confirmed by analysis of (13)C positional enrichment in 3HV. Notably, (13)C metabolic flux analysis showed that the citramalate/2-oxobutyrate pathway (53.0% flux) and the 3-hydroxypropionate pathway (30.6% flux) were the two main generators of propionyl-CoA from glucose. In addition, genetic perturbation on the transcriptome of the ΔphaEC mutant (deficient in PHBV accumulation) revealed that a considerable number of genes in the four propionyl-CoA synthetic pathways were significantly downregulated. We determined for the first time four propionyl-CoA-supplying pathways for PHBV production in haloarchaea, particularly including a new 3-hydroxypropionate pathway. These results would provide novel strategies for the production of PHBV with controllable 3HV molar fraction. | Zarzycki J, Kerfeld CA (2013)
The crystal structures of the tri-functional Chloroflexus aurantiacus and bi-functional Rhodobacter sphaeroides malyl-CoA lyases and comparison with CitE-like superfamily enzymes and malate synthases.
BMC structural biology 13, 28 [PubMed:24206647]
[show Abstract]
BackgroundMalyl-CoA lyase (MCL) is a promiscuous carbon-carbon bond lyase that catalyzes the reversible cleavage of structurally related Coenzyme A (CoA) thioesters. This enzyme plays a crucial, multifunctional role in the 3-hydroxypropionate bi-cycle for autotrophic CO2 fixation in Chloroflexus aurantiacus. A second, phylogenetically distinct MCL from Rhodobacter sphaeroides is involved in the ethylmalonyl-CoA pathway for acetate assimilation. Both MCLs belong to the large superfamily of CitE-like enzymes, which includes the name-giving β-subunit of citrate lyase (CitE), malyl-CoA thioesterases and other enzymes of unknown physiological function. The CitE-like enzyme superfamily also bears sequence and structural resemblance to the malate synthases. All of these different enzymes share highly conserved catalytic residues, although they catalyze distinctly different reactions: C-C bond formation and cleavage, thioester hydrolysis, or both (the malate synthases).ResultsHere we report the first crystal structures of MCLs from two different phylogenetic subgroups in apo- and substrate-bound forms. Both the C. aurantiacus and the R. sphaeroides MCL contain elaborations on the canonical β8/α8 TIM barrel fold and form hexameric assemblies. Upon ligand binding, changes in the C-terminal domains of the MCLs result in closing of the active site, with the C-terminal domain of one monomer forming a lid over and contributing side chains to the active site of the adjacent monomer. The distinctive features of the two MCL subgroups were compared to known structures of other CitE-like superfamily enzymes and to malate synthases, providing insight into the structural subtleties that underlie the functional versatility of these enzymes.ConclusionsAlthough the C. aurantiacus and the R. sphaeroides MCLs have divergent primary structures (~37% identical), their tertiary and quaternary structures are very similar. It can be assumed that the C-C bond formation catalyzed by the MCLs occurs as proposed for malate synthases. However, a comparison of the two MCL structures with known malate synthases raised the question why the MCLs are not also able to hydrolyze CoA thioester bonds. Our results suggest the previously proposed reaction mechanism for malate synthases may be incomplete or not entirely correct. Further studies involving site-directed mutagenesis based on these structures may be required to solve this puzzling question. | Diacovich L, Mitchell DL, Pham H, Gago G, Melgar MM, Khosla C, Gramajo H, Tsai SC (2004)
Crystal structure of the beta-subunit of acyl-CoA carboxylase: structure-based engineering of substrate specificity.
Biochemistry 43, 14027-14036 [PubMed:15518551]
[show Abstract]
Acetyl-CoA carboxylase (ACC) and propionyl-CoA carboxylase (PCC) catalyze the carboxylation of acetyl- and propionyl-CoA to generate malonyl- and methylmalonyl-CoA, respectively. Understanding the substrate specificity of ACC and PCC will (1) help in the development of novel structure-based inhibitors that are potential therapeutics against obesity, cancer, and infectious disease and (2) facilitate bioengineering to provide novel extender units for polyketide biosynthesis. ACC and PCC in Streptomyces coelicolor are multisubunit complexes. The core catalytic beta-subunits, PccB and AccB, are 360 kDa homohexamers, catalyzing the transcarboxylation between biotin and acyl-CoAs. Apo and substrate-bound crystal structures of PccB hexamers were determined to 2.0-2.8 A. The hexamer assembly forms a ring-shaped complex. The hydrophobic, highly conserved biotin-binding pocket was identified for the first time. Biotin and propionyl-CoA bind perpendicular to each other in the active site, where two oxyanion holes were identified. N1 of biotin is proposed to be the active site base. Structure-based mutagenesis at a single residue of PccB and AccB allowed interconversion of the substrate specificity of ACC and PCC. The di-domain, dimeric interaction is crucial for enzyme catalysis, stability, and substrate specificity; these features are also highly conserved among biotin-dependent carboxyltransferases. Our findings enable bioengineering of the acyl-CoA carboxylase (ACCase) substrate specificity to provide novel extender units for the combinatorial biosynthesis of polyketides. | Zhang YQ, Brock M, Keller NP (2004)
Connection of propionyl-CoA metabolism to polyketide biosynthesis in Aspergillus nidulans.
Genetics 168, 785-794 [PubMed:15514053]
[show Abstract]
Propionyl-CoA is an intermediate metabolite produced through a variety of pathways including thioesterification of propionate and catabolism of odd chain fatty acids and select amino acids. Previously, we found that disruption of the methylcitrate synthase gene, mcsA, which blocks propionyl-CoA utilization, as well as growth on propionate impaired production of several polyketides-molecules typically derived from acetyl-CoA and malonyl-CoA-including sterigmatocystin (ST), a potent carcinogen, and the conidiospore pigment. Here we describe three lines of evidence that demonstrate that excessive propionyl-CoA levels in the cell can inhibit polyketide synthesis. First, inactivation of a putative propionyl-CoA synthase, PcsA, which converts propionate to propionyl-CoA, restored polyketide production and reduced cellular propionyl-CoA content in a DeltamcsA background. Second, inactivation of the acetyl-CoA synthase, FacA, which is also involved in propionate utilization, restored polyketide production in the DeltamcsA background. Third, fungal growth on several compounds (e.g., heptadecanoic acid, isoleucine, and methionine) whose catabolism includes the formation of propionyl-CoA, were found to inhibit ST and conidiospore pigment production. These results demonstrate that excessive propionyl-CoA levels in the cell can inhibit polyketide synthesis. | Palacios S, Starai VJ, Escalante-Semerena JC (2003)
Propionyl coenzyme A is a common intermediate in the 1,2-propanediol and propionate catabolic pathways needed for expression of the prpBCDE operon during growth of Salmonella enterica on 1,2-propanediol.
Journal of bacteriology 185, 2802-2810 [PubMed:12700259]
[show Abstract]
The studies reported here identify propionyl coenzyme A (propionyl-CoA) as the common intermediate in the 1,2-propanediol and propionate catabolic pathways of Salmonella enterica serovar Typhimurium LT2. Growth on 1,2-propanediol as a carbon and energy source led to the formation and excretion of propionate, whose activation to propionyl-CoA relied on the activities of the propionate kinase (PduW)/phosphotransacetylase (Pta) enzyme system and the CobB sirtuin-controlled acetyl-CoA and propionyl-CoA (Acs, PrpE) synthetases. The different affinities of these systems for propionate ensure sufficient synthesis of propionyl-CoA to support wild-type growth of S. enterica under low or high concentrations of propionate in the environment. These redundant systems of propionyl-CoA synthesis are needed because the prpE gene encoding the propionyl-CoA synthetase enzyme is part of the prpBCDE operon under the control of the PrpR regulatory protein, which needs 2-methylcitrate as a coactivator. Because the synthesis of 2-methylcitrate by PrpC (i.e., the 2-methylcitrate synthase enzyme) requires propionyl-CoA as a substrate, the level of propionyl-CoA needs to be raised by the Acs or PduW-Pta system before 2-methylcitrate can be synthesized and prpBCDE transcription can be activated. | Reszko AE, Kasumov T, Pierce BA, David F, Hoppel CL, Stanley WC, Des Rosiers C, Brunengraber H (2003)
Assessing the reversibility of the anaplerotic reactions of the propionyl-CoA pathway in heart and liver.
The Journal of biological chemistry 278, 34959-34965 [PubMed:12824185]
[show Abstract]
While a number of studies underline the importance of anaplerotic pathways for hepatic biosynthetic functions and cardiac contractile activity, much remains to be learned about the sites and regulation of anaplerosis in these tissues. As part of a study on the regulation of anaplerosis from propionyl-CoA precursors in rat livers and hearts, we investigated the degree of reversibility of the reactions of the propionyl-CoA pathway. Label was introduced into the pathway via NaH13CO3, [U-13C3]propionate, or [U-13C3]lactate + [U-13C3]pyruvate, under various concentrations of propionate. The mass isotopomer distributions of propionyl-CoA, methylmalonyl-CoA, and succinyl-CoA revealed that, in intact livers and hearts, (i) the propionyl-CoA carboxylase reaction is slightly reversible only at low propionyl-CoA flux, (ii) the methylmalonyl-CoA racemase reaction keeps the methylmalonyl-CoA enantiomers in isotopic equilibrium under all conditions tested, and (iii) the methylmalonyl-CoA mutase reaction is reversible, but its reversibility decreases as the flow of propionyl-CoA increases. The thermodynamic dis-equilibrium of the combined reactions of the propionyl-CoA pathway explains the effectiveness of anaplerosis from propionyl-CoA precursors such as heptanoate. | Kamoun P (1992)
Valine is a precursor of propionyl-CoA.
Trends in biochemical sciences 17, 175-176 [PubMed:1595124]
[show Abstract]
For some time the metabolism of valine has been misrepresented by several biochemistry textbooks. This article demonstrates that propionyl-CoA occurs as an intermediate in the valine metabolic pathway before the formation of methylmalonyl CoA. | Krahenbuhl S, Brass EP (1991)
Inhibition of hepatic propionyl-CoA synthetase activity by organic acids. Reversal of propionate inhibition of pyruvate metabolism.
Biochemical pharmacology 41, 1015-1023 [PubMed:2009071]
[show Abstract]
Intracellular accumulation of propionyl-CoA is associated with impairment of important hepatic metabolic pathways. Since propionate absorbed from the intestine can be converted to propionyl-CoA in the liver, inhibition of propionyl-CoA synthesis from propionate and CoA may provide a strategy for decreasing toxicity from plasma propionate. Therefore, inhibition of propionyl-CoA formation by several organic acids was investigated. In isolated, solubilized mitochondria, octanoate, butyrate, salicylate and p-nitrobenzoate inhibited propionyl-CoA synthesis. Octanoate was the most potent inhibitor of propionyl-CoA synthetase activity and had a Ki of 58 microM. In isolated hepatocytes, octanoate inhibited propionate oxidation in a concentration-dependent manner. Consistent with previous studies, propionate (1.0 mM) inhibited the rates of 14CO2 formation from [1-14C]pyruvate (10 mM) to 55% of the control values in the hepatocyte system. Octanoate (0.8 mM) had no effect on [1-14C]pyruvate oxidation under control conditions, but increased 14CO2 formation from pyruvate to 88% of the control values in the presence of 1.0 mM propionate. Reversal of propionate inhibition of pyruvate oxidation by octanoate was associated with a 44% decrease in hepatocyte propionyl-CoA content. In contrast, while pyruvate oxidation rates were decreased to 53% of control rates in the presence of 10 mM propionylcarnitine, octanoate stimulated pyruvate oxidation under these conditions only to 67% of control levels. In conclusion, mitochondrial propionyl-CoA synthetase activity and hepatocyte propionyl-CoA accumulation can be inhibited by octanoate with consequent decreased propionate oxidation and toxicity in intact hepatocytes. The reversal by octanoate of propionate's inhibition of cellular metabolism may be useful in reducing tissue toxicity from circulating propionate. | Davies SE, Iles RA, Stacey TE, de Sousa C, Chalmers RA (1991)
Carnitine therapy and metabolism in the disorders of propionyl-CoA metabolism studied using 1H-NMR spectroscopy.
Clinica chimica acta; international journal of clinical chemistry 204, 263-277 [PubMed:1819469]
[show Abstract]
1H-NMR spectroscopy has been used to study metabolic perturbations in patients with disorders of propionyl-CoA metabolism during the administration of oral and intravenous L-carnitine. The administration of L-carnitine either in the form of a challenge or as a therapeutic measure resulted in an increased excretion of propionylcarnitine, consistent with the removal of accumulated intramitochondrial propionyl-CoA esters. Additionally, during the therapeutic administration of L-carnitine excretion of acetylcarnitine occurred, coincident with an improvement in clinical condition and confirming the intracellular propionyl-CoA depletion. An additional benefit from the formation of acylcarnitines may be an accompanying intracellular alkalinisation. | Maruyama K, Kitamura H (1985)
Mechanisms of growth inhibition by propionate and restoration of the growth by sodium bicarbonate or acetate in Rhodopseudomonas sphaeroides S.
Journal of biochemistry 98, 819-824 [PubMed:3003041]
[show Abstract]
Mechanisms of growth inhibition by propionate on the growth of Rhodopseudomonas sphaeroides were studied. Partially purified pyruvate dehydrogenase complex (PDC) from R. sphaeroides was inhibited by propionyl-CoA, one of the metabolic intermediates of propionate, while propionate itself did not inhibit the enzyme. This suggests that the inhibitor of the growth in vivo is not propionate but propionyl-CoA. The inhibition by propionyl-CoA was competitive with respect to coenzyme A concentration. The K1 value for propionyl-CoA was 0.84 mM. Addition of NaHCO3, which restored the growth of this bacterium in the presence of propionate, increased the rate of propionate incorporation by 1.7-fold and decreased the intracellular level of propionyl-CoA by half. These findings suggest that HCO3-ion lowers the level of propionyl-CoA by accelerating its carboxylation reaction, which is catalyzed by propionyl-CoA carboxylase. Effects of NaHCO3 and acetate on the growth restoration were also studied by the use of propionyl-CoA carboxylase-deficient mutants. NaHCO3 did not restore the growth of the mutants, indicating an essential role of propionyl-CoA carboxylase on the restoration of growth by NaHCO3 as suggested above. Addition of acetate restores the growth of the mutants in the presence of propionate. Acetate probably restores the growth by supplying acetyl-CoA. |
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