3'-dephospho-CoA (CHEBI:15468)

ChEBI > Main

CHEBI:15468 - 3'-dephospho-CoA

Main

ChEBI Ontology

Automatic Xrefs

Reactions

Pathways

Models

ChEBI Name	3'-dephospho-CoA

ChEBI ID	CHEBI:15468

Definition	An adenosine 5'-phosphate that is coenzyme A in which the phosphate group at position 3' has been replaced by a hydrogen atom. It is an intermediate metabolite in pantothenate and CoA biosynthesis.

Stars	This entity has been manually annotated by the ChEBI Team.

Secondary ChEBI IDs	CHEBI:41614, CHEBI:11793, CHEBI:14124, CHEBI:23642, CHEBI:4436

Supplier Information	ZINC000008551261

Download	Molfile XML SDF

more structures >>

call loadScript javascripts\jsmol\core\package.js

call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode

call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js

Jmol JavaScript applet jmolApplet0_object__0521433403377896__ initializing

getValue debug = null

getValue logLevel = null

getValue allowjavascript = null

AppletRegistry.checkIn(jmolApplet0_object__0521433403377896__)

call loadScript javascripts\jsmol\core\corestate.z.js

viewerOptions:

{ "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:4436","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__0521433403377896__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"0521433403377896","bgcolor":"#000" }

Jmol Version: 13.2.7 $Date: 2013-10-01 11:35:15 -0500 (Tue, 01 Oct 2013) $

java.vendor: j2s

java.version: 0.0

os.name: j2s

Access: ALL

memory: 0.0/0.0

processors available: 1

useCommandThread: false

appletId:jmolApplet0_object (signed)

starting HoverWatcher_1

getValue emulate = null

defaults = "Jmol"

getValue boxbgcolor = null

getValue bgcolor = #000

backgroundColor = "#000"

getValue ANIMFRAMECallback = null

getValue APPLETREADYCallback = Jmol._readyCallback

APPLETREADYCallback = "Jmol._readyCallback"

getValue ATOMMOVEDCallback = null

getValue CLICKCallback = null

getValue ECHOCallback = null

getValue ERRORCallback = null

getValue EVALCallback = null

getValue HOVERCallback = null

getValue LOADSTRUCTCallback = null

getValue MEASURECallback = null

getValue MESSAGECallback = null

getValue MINIMIZATIONCallback = null

getValue PICKCallback = null

getValue RESIZECallback = null

getValue SCRIPTCallback = null

getValue SYNCCallback = null

getValue STRUCTUREMODIFIEDCallback = null

getValue doTranslate = null

language=en_US

getValue popupMenu = null

getValue script = null

Jmol applet jmolApplet0_object__0521433403377896__ 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

COD - Ideal conformer

Mrv1927 06082116033D

starting HoverWatcher_5

Time for openFile(COD - Ideal conformer

Mrv1927 06082116033D

79 81 0 0 0 0 999 V2000

3.9590 1.4830 -9.3330 N 0 0 0 0 0 0 0 0 0 0 0 0

2.7100 1.2730 -9.7100 C 0 0 0 0 0 0 0 0 0 0 0 0

1.7770 0.8730 -8.8720 N 0 0 0 0 0 0 0 0 0 0 0 0

2.0640 0.6570 -7.5920 C 0 0 0 0 0 0 0 0 0 0 0 0

3.3770 0.8720 -7.1400 C 0 0 0 0 0 0 0 0 0 0 0 0

4.3380 1.2980 -8.0730 C 0 0 0 0 0 0 0 0 0 0 0 0

5.6480 1.5200 -7.6880 N 0 0 0 0 0 0 0 0 0 0 0 0

3.3950 0.5890 -5.8160 N 0 0 0 0 0 0 0 0 0 0 0 0

2.2040 0.2280 -5.4340 C 0 0 0 0 0 0 0 0 0 0 0 0

1.3460 0.2570 -6.4930 N 0 0 0 0 0 0 0 0 0 0 0 0

-0.0780 -0.0820 -6.4640 C 0 0 1 0 0 0 0 0 0 0 0 0

-0.2820 -1.6080 -6.6430 C 0 0 2 0 0 0 0 0 0 0 0 0

-0.3270 -1.9570 -8.0280 O 0 0 0 0 0 0 0 0 0 0 0 0

-1.6630 -1.8310 -5.9720 C 0 0 2 0 0 0 0 0 0 0 0 0

-2.6980 -1.8670 -6.9560 O 0 0 0 0 0 0 0 0 0 0 0 0

-1.8300 -0.6100 -5.0460 C 0 0 2 0 0 0 0 0 0 0 0 0

-0.6370 0.1820 -5.1600 O 0 0 0 0 0 0 0 0 0 0 0 0

-2.0110 -1.0750 -3.6000 C 0 0 2 0 0 0 0 0 0 0 0 0

-2.1580 0.0630 -2.7490 O 0 0 0 0 0 0 0 0 0 0 0 0

-2.3430 -0.4960 -1.2510 P 0 0 1 0 0 5 0 0 0 0 0 0

-3.6510 -1.4320 -1.1850 O 0 0 0 0 0 0 0 0 0 0 0 0

-1.1510 -1.2860 -0.8690 O 0 0 0 0 0 0 0 0 0 0 0 0

-2.5160 0.7390 -0.2330 O 0 0 0 0 0 0 0 0 0 0 0 0

-2.6950 0.1100 1.2370 P 0 0 1 0 0 5 0 0 0 0 0 0

-3.9970 -0.8360 1.2610 O 0 0 0 0 0 0 0 0 0 0 0 0

-1.4980 -0.6890 1.5800 O 0 0 0 0 0 0 0 0 0 0 0 0

-2.8740 1.2960 2.3100 O 0 0 0 0 0 0 0 0 0 0 0 0

-3.0270 0.6770 3.5890 C 0 0 2 0 0 0 0 0 0 0 0 0

-3.2020 1.7550 4.6600 C 0 0 1 0 0 0 0 0 0 0 0 0

-1.9700 2.6620 4.6770 C 0 0 0 0 0 0 0 0 0 0 0 0

-4.4450 2.5900 4.3450 C 0 0 0 0 0 0 0 0 0 0 0 0

-3.3670 1.0920 6.0290 C 0 0 1 0 0 0 0 0 0 0 0 0

-4.5900 0.3540 6.0570 O 0 0 0 0 0 0 0 0 0 0 0 0

-2.2110 0.1580 6.2760 C 0 0 0 0 0 0 0 0 0 0 0 0

-2.3870 -1.0410 6.2630 O 0 0 0 0 0 0 0 0 0 0 0 0

-0.9800 0.6550 6.5120 N 0 0 0 0 0 0 0 0 0 0 0 0

0.1260 -0.2490 6.8330 C 0 0 1 0 0 0 0 0 0 0 0 0

1.4020 0.5650 7.0540 C 0 0 1 0 0 0 0 0 0 0 0 0

2.5410 -0.3650 7.3830 C 0 0 0 0 0 0 0 0 0 0 0 0

2.3500 -1.5610 7.4360 O 0 0 0 0 0 0 0 0 0 0 0 0

3.7710 0.1320 7.6190 N 0 0 0 0 0 0 0 0 0 0 0 0

4.8780 -0.7720 7.9400 C 0 0 1 0 0 0 0 0 0 0 0 0

6.1540 0.0410 8.1610 C 0 0 1 0 0 0 0 0 0 0 0 0

7.5250 -1.0780 8.5580 S 0 0 0 0 0 0 0 0 0 0 0 0

2.4450 1.4360 -10.7440 H 0 0 0 0 0 0 0 0 0 0 0 0

6.3020 1.8150 -8.3410 H 0 0 0 0 0 0 0 0 0 0 0 0

5.9130 1.3820 -6.7650 H 0 0 0 0 0 0 0 0 0 0 0 0

1.9350 -0.0530 -4.4260 H 0 0 0 0 0 0 0 0 0 0 0 0

-0.6180 0.4700 -7.2330 H 0 0 0 0 0 0 0 0 0 0 0 0

0.4970 -2.1680 -6.1270 H 0 0 0 0 0 0 0 0 0 0 0 0

-0.4560 -2.9150 -8.0700 H 0 0 0 0 0 0 0 0 0 0 0 0

-1.6590 -2.7530 -5.3900 H 0 0 0 0 0 0 0 0 0 0 0 0

-2.5040 -2.6140 -7.5380 H 0 0 0 0 0 0 0 0 0 0 0 0

-2.6950 -0.0250 -5.3580 H 0 0 0 0 0 0 0 0 0 0 0 0

-1.1370 -1.6490 -3.2910 H 0 0 0 0 0 0 0 0 0 0 0 0

-2.9010 -1.7000 -3.5270 H 0 0 0 0 0 0 0 0 0 0 0 0

-4.4030 -0.8800 -1.4400 H 0 0 0 0 0 0 0 0 0 0 0 0

-4.7530 -0.2770 1.0320 H 0 0 0 0 0 0 0 0 0 0 0 0

-2.1410 0.0830 3.8130 H 0 0 0 0 0 0 0 0 0 0 0 0

-3.9050 0.0310 3.5760 H 0 0 0 0 0 0 0 0 0 0 0 0

-1.0720 2.0530 4.7780 H 0 0 0 0 0 0 0 0 0 0 0 0

-1.9230 3.2280 3.7470 H 0 0 0 0 0 0 0 0 0 0 0 0

-2.0380 3.3510 5.5190 H 0 0 0 0 0 0 0 0 0 0 0 0

-5.3310 1.9570 4.3990 H 0 0 0 0 0 0 0 0 0 0 0 0

-4.5330 3.4000 5.0690 H 0 0 0 0 0 0 0 0 0 0 0 0

-4.3580 3.0070 3.3420 H 0 0 0 0 0 0 0 0 0 0 0 0

-3.3870 1.8590 6.8040 H 0 0 0 0 0 0 0 0 0 0 0 0

-4.5310 -0.3100 5.3580 H 0 0 0 0 0 0 0 0 0 0 0 0

-0.8280 1.6120 6.4700 H 0 0 0 0 0 0 0 0 0 0 0 0

-0.1110 -0.8060 7.7390 H 0 0 0 0 0 0 0 0 0 0 0 0

0.2770 -0.9440 6.0070 H 0 0 0 0 0 0 0 0 0 0 0 0

1.6390 1.1220 6.1480 H 0 0 0 0 0 0 0 0 0 0 0 0

1.2510 1.2600 7.8790 H 0 0 0 0 0 0 0 0 0 0 0 0

3.9230 1.0890 7.5770 H 0 0 0 0 0 0 0 0 0 0 0 0

4.6410 -1.3290 8.8460 H 0 0 0 0 0 0 0 0 0 0 0 0

5.0290 -1.4680 7.1140 H 0 0 0 0 0 0 0 0 0 0 0 0

6.3910 0.5990 7.2550 H 0 0 0 0 0 0 0 0 0 0 0 0

6.0030 0.7370 8.9860 H 0 0 0 0 0 0 0 0 0 0 0 0

8.5190 -0.1850 8.7090 H 0 0 0 0 0 0 0 0 0 0 0 0

1 2 2 0 0 0 0

1 6 1 0 0 0 0

2 3 1 0 0 0 0

2 45 1 0 0 0 0

3 4 2 0 0 0 0

4 5 1 0 0 0 0

4 10 1 0 0 0 0

5 6 2 0 0 0 0

5 8 1 0 0 0 0

6 7 1 0 0 0 0

7 46 1 0 0 0 0

7 47 1 0 0 0 0

8 9 2 0 0 0 0

9 10 1 0 0 0 0

9 48 1 0 0 0 0

10 11 1 0 0 0 0

11 12 1 0 0 0 0

11 17 1 0 0 0 0

11 49 1 6 0 0 0

12 13 1 0 0 0 0

12 14 1 0 0 0 0

12 50 1 1 0 0 0

13 51 1 0 0 0 0

14 15 1 0 0 0 0

14 16 1 0 0 0 0

14 52 1 1 0 0 0

15 53 1 0 0 0 0

16 17 1 0 0 0 0

16 18 1 0 0 0 0

16 54 1 6 0 0 0

18 19 1 0 0 0 0

18 55 1 0 0 0 0

18 56 1 0 0 0 0

20 19 1 6 0 0 0

20 21 1 0 0 0 0

20 22 2 0 0 0 0

20 23 1 0 0 0 0

21 57 1 0 0 0 0

24 23 1 6 0 0 0

24 25 1 0 0 0 0

24 26 2 0 0 0 0

24 27 1 0 0 0 0

25 58 1 0 0 0 0

27 28 1 0 0 0 0

28 29 1 0 0 0 0

28 59 1 0 0 0 0

28 60 1 0 0 0 0

29 30 1 0 0 0 0

29 31 1 0 0 0 0

29 32 1 0 0 0 0

30 61 1 0 0 0 0

30 62 1 0 0 0 0

30 63 1 0 0 0 0

31 64 1 0 0 0 0

31 65 1 0 0 0 0

31 66 1 0 0 0 0

32 33 1 0 0 0 0

32 34 1 0 0 0 0

32 67 1 1 0 0 0

33 68 1 0 0 0 0

34 35 2 0 0 0 0

34 36 1 0 0 0 0

36 37 1 0 0 0 0

36 69 1 0 0 0 0

37 38 1 0 0 0 0

37 70 1 0 0 0 0

37 71 1 0 0 0 0

38 39 1 0 0 0 0

38 72 1 0 0 0 0

38 73 1 0 0 0 0

39 40 2 0 0 0 0

39 41 1 0 0 0 0

41 42 1 0 0 0 0

41 74 1 0 0 0 0

42 43 1 0 0 0 0

42 75 1 0 0 0 0

42 76 1 0 0 0 0

43 44 1 0 0 0 0

43 77 1 0 0 0 0

43 78 1 0 0 0 0

44 79 1 0 0 0 0

M END): 19 ms

reading 79 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

79 atoms created

ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation

Script completed

Jmol script terminated

Molfile expand

Formula

C21H35N7O13P2S

Net Charge

Average Mass

687.550

Monoisotopic Mass

687.14888

InChI

InChI=1S/C21H35N7O13P2S/c1-21(2,16(32)19(33)24-4-3-12(29)23-5-6-44)8-39-43(36,37)41-42(34,35)38-7-11-14(30)15(31)20(40-11)28-10-27-13-17(22)25-9-26-18(13)28/h9-11,14-16,20,30-32,44H,3-8H2,1-2H3,(H,23,29)(H,24,33)(H,34,35)(H,36,37)(H2,22,25,26)/t11-,14-,15-,16+,20-/m1/s1

InChIKey

KDTSHFARGAKYJN-IBOSZNHHSA-N

SMILES

CC(C)(COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1O)N1C=NC2=C1N=CN=C2N)[C@@H](O)C(=O)NCCC(=O)NCCS

Metabolite of Species	Details
Mus musculus (NCBI:txid10090)	Source: BioModels - MODEL1507180067 See: PubMed
Mus musculus (NCBI:txid10090)	From MetaboLights See: MetaboLights Study
Brassica napus (NCBI:txid3708)	From MetaboLights See: MetaboLights Study
Escherichia coli (NCBI:txid562)	See: DOI
Escherichia coli (NCBI:txid562)	See: PubMed
Homo sapiens (NCBI:txid9606)	See: PubMed

Roles Classification
Biological Role(s):	Escherichia coli metabolite Any bacterial metabolite produced during a metabolic reaction in Escherichia coli. human metabolite Any mammalian metabolite produced during a metabolic reaction in humans (Homo sapiens). mouse metabolite Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).

View more via ChEBI Ontology

ChEBI Ontology
Outgoing	3'-dephospho-CoA (CHEBI:15468) has functional parent coenzyme A (CHEBI:15346) 3'-dephospho-CoA (CHEBI:15468) has role Escherichia coli metabolite (CHEBI:76971) 3'-dephospho-CoA (CHEBI:15468) has role human metabolite (CHEBI:77746) 3'-dephospho-CoA (CHEBI:15468) has role mouse metabolite (CHEBI:75771) 3'-dephospho-CoA (CHEBI:15468) is a adenosine 5'-phosphate (CHEBI:37096) 3'-dephospho-CoA (CHEBI:15468) is conjugate acid of 3'-dephospho-CoA(2−) (CHEBI:57328)

Incoming	3'-dephospho-CoA(2−) (CHEBI:57328) is conjugate base of 3'-dephospho-CoA (CHEBI:15468)

IUPAC Name

adenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-({3-oxo-3-[(2-sulfanylethyl)amino]propyl}amino)butyl] dihydrogen diphosphate}

Synonyms	Sources
dephospho coenzyme A	PDBeChem
Dephospho-CoA	KEGG COMPOUND
Dephosphocoenzyme A	KEGG COMPOUND

Manual Xrefs	Databases
C00007257	KNApSAcK
C00882	KEGG COMPOUND
COD	PDBeChem
DB03170	DrugBank
ECMDB01373	ECMDB
FDB022585	FooDB
HMDB0001373	HMDB
LMFA07050315	LIPID MAPS
YMDB00664	YMDB
View more database links

Registry Number	Type	Source
3633-59-8	CAS Registry Number	ChemIDplus

Citations

Shimosaka T, Makarova KS, Koonin EV, Atomi H (2019)
Identification of Dephospho-Coenzyme A (Dephospho-CoA) Kinase in Thermococcus kodakarensis and Elucidation of the Entire CoA Biosynthesis Pathway in Archaea.
mBio 10, e01146-19 [PubMed:31337720]
[show Abstract]
Dephospho-coenzyme A (dephospho-CoA) kinase (DPCK) catalyzes the ATP-dependent phosphorylation of dephospho-CoA, the final step in coenzyme A (CoA) biosynthesis. DPCK has been identified and characterized in bacteria and eukaryotes but not in archaea. The hyperthermophilic archaeon Thermococcus kodakarensis encodes two homologs of bacterial DPCK and the DPCK domain of eukaryotic CoA synthase, TK1334 and TK2192. We purified the recombinant TK1334 and TK2192 proteins and found that they lacked DPCK activity. Bioinformatic analyses showed that, in several archaea, the uncharacterized gene from arCOG04076 protein is fused with the gene for phosphopantetheine adenylyltransferase (PPAT), which catalyzes the reaction upstream of the DPCK reaction in CoA biosynthesis. This observation suggested that members of arCOG04076, both fused to PPAT and standalone, could be the missing archaeal DPCKs. We purified the recombinant TK1697 protein, a standalone member of arCOG04076 from T. kodakarensis, and demonstrated its GTP-dependent DPCK activity. Disruption of the TK1697 resulted in CoA auxotrophy, indicating that TK1697 encodes a DPCK that contributes to CoA biosynthesis in T. kodakarensis TK1697 homologs are widely distributed in archaea, suggesting that the arCOG04076 protein represents a novel family of DPCK that is not homologous to bacterial and eukaryotic DPCKs but is distantly related to bacterial and eukaryotic thiamine pyrophosphokinases. We also constructed and characterized gene disruption strains of TK0517 and TK2128, homologs of bifunctional phosphopantothenoylcysteine synthetase-phosphopantothenoylcysteine decarboxylase and PPAT, respectively. Both strains displayed CoA auxotrophy, indicating their contribution to CoA biosynthesis. Taken together with previous studies, the results experimentally validate the entire CoA biosynthesis pathway in T. kodakarensisIMPORTANCE CoA is utilized in a wide range of metabolic pathways, and its biosynthesis is essential for all life. Pathways for CoA biosynthesis in bacteria and eukaryotes have been established. In archaea, however, the enzyme that catalyzes the final step in CoA biosynthesis, dephospho-CoA kinase (DPCK), had not been identified. In the present study, bioinformatic analyses identified a candidate for the DPCK in archaea, which was biochemically and genetically confirmed in the hyperthermophilic archaeon Thermococcus kodakarensis Genetic analyses on genes presumed to encode bifunctional phosphopantothenoylcysteine synthetase-phosphopantothenoylcysteine decarboxylase and phosphopantetheine adenylyltransferase confirmed their involvement in CoA biosynthesis. Taken together with previous studies, the results reveal the entire pathway for CoA biosynthesis in a single archaeon and provide insight into the different mechanisms of CoA biosynthesis and their distribution in nature.

Kim YH, Gogerty DS, Plapp BV (2018)
Substitutions of a buried glutamate residue hinder the conformational change in horse liver alcohol dehydrogenase and yield a surprising complex with endogenous 3'-Dephosphocoenzyme A.
Archives of biochemistry and biophysics 653, 97-106 [PubMed:30018019]
[show Abstract]

Thomas SE, Mendes V, Kim SY, Malhotra S, Ochoa-Montaño B, Blaszczyk M, Blundell TL (2017)
Structural Biology and the Design of New Therapeutics: From HIV and Cancer to Mycobacterial Infections: A Paper Dedicated to John Kendrew.
Journal of molecular biology 429, 2677-2693 [PubMed:28648615]
[show Abstract]

Bird JG, Zhang Y, Tian Y, Panova N, Barvík I, Greene L, Liu M, Buckley B, Krásný L, Lee JK, Kaplan CD, Ebright RH, Nickels BE (2016)
The mechanism of RNA 5′ capping with NAD+, NADH and desphospho-CoA.
Nature 535, 444-447 [PubMed:27383794]
[show Abstract]

Yu D, Chen X, Xu Z, Ge H (2014)
Crystallization and preliminary X-ray characterization of the dephospho-CoA kinase from Legionella pneumophila.
Acta crystallographica. Section F, Structural biology communications 70, 608-610 [PubMed:24817720]
[show Abstract]

Gong X, Chen X, Yu D, Zhang N, Zhu Z, Niu L, Mao Y, Ge H (2014)
Crystal structure of Legionella pneumophila dephospho-CoA kinase reveals a non-canonical conformation of P-loop.
Journal of structural biology 188, 233-239 [PubMed:25449315]
[show Abstract]

Edwards TE, Leibly DJ, Bhandari J, Statnekov JB, Phan I, Dieterich SH, Abendroth J, Staker BL, Van Voorhis WC, Myler PJ, Stewart LJ (2011)
Structures of phosphopantetheine adenylyltransferase from Burkholderia pseudomallei.
Acta crystallographica. Section F, Structural biology and crystallization communications 67, 1032-1037 [PubMed:21904046]
[show Abstract]

Walia G, Gajendar K, Surolia A (2011)
Identification of critical residues of the mycobacterial dephosphocoenzyme a kinase by site-directed mutagenesis.
PloS one 6, e15228 [PubMed:21264299]
[show Abstract]
Dephosphocoenzyme A kinase performs the transfer of the γ-phosphate of ATP to dephosphocoenzyme A, catalyzing the last step of coenzyme A biosynthesis. This enzyme belongs to the P-loop-containing NTP hydrolase superfamily, all members of which posses a three domain topology consisting of a CoA domain that binds the acceptor substrate, the nucleotide binding domain and the lid domain. Differences in the enzymatic organization and regulation between the human and mycobacterial counterparts, have pointed out the tubercular CoaE as a high confidence drug target (HAMAP database). Unfortunately the absence of a three-dimensional crystal structure of the enzyme, either alone or complexed with either of its substrates/regulators, leaves both the reaction mechanism unidentified and the chief players involved in substrate binding, stabilization and catalysis unknown. Based on homology modeling and sequence analysis, we chose residues in the three functional domains of the enzyme to assess their contributions to ligand binding and catalysis using site-directed mutagenesis. Systematically mutating the residues from the P-loop and the nucleotide-binding site identified Lys14 and Arg140 in ATP binding and the stabilization of the phosphoryl intermediate during the phosphotransfer reaction. Mutagenesis of Asp32 and Arg140 showed catalytic efficiencies less than 5-10% of the wild type, indicating the pivotal roles played by these residues in catalysis. Non-conservative substitution of the Leu114 residue identifies this leucine as the critical residue from the hydrophobic cleft involved in leading substrate, DCoA binding. We show that the mycobacterial enzyme requires the Mg(2+) for its catalytic activity. The binding energetics of the interactions of the mutant enzymes with the substrates were characterized in terms of their enthalpic and entropic contributions by ITC, providing a complete picture of the effects of the mutations on activity. The properties of mutants defective in substrate recognition were consistent with the ordered sequential mechanism of substrate addition for CoaE.

Walia G, Kumar P, Surolia A (2009)
The role of UPF0157 in the folding of M. tuberculosis dephosphocoenzyme A kinase and the regulation of the latter by CTP.
PloS one 4, e7645 [PubMed:19876400]
[show Abstract]

Background

Targeting the biosynthetic pathway of Coenzyme A (CoA) for drug development will compromise multiple cellular functions of the tubercular pathogen simultaneously. Structural divergence in the organization of the penultimate and final enzymes of CoA biosynthesis in the host and pathogen and the differences in their regulation mark out the final enzyme, dephosphocoenzyme A kinase (CoaE) as a potential drug target.

Methodology/principal findings

We report here a complete biochemical and biophysical characterization of the M. tuberculosis CoaE, an enzyme essential for the pathogen's survival, elucidating for the first time the interactions of a dephosphocoenzyme A kinase with its substrates, dephosphocoenzyme A and ATP; its product, CoA and an intrinsic yet novel inhibitor, CTP, which helps modulate the enzyme's kinetic capabilities providing interesting insights into the regulation of CoaE activity. We show that the mycobacterial enzyme is almost 21 times more catalytically proficient than its counterparts in other prokaryotes. ITC measurements illustrate that the enzyme follows an ordered mechanism of substrate addition with DCoA as the leading substrate and ATP following in tow. Kinetic and ITC experiments demonstrate that though CTP binds strongly to the enzyme, it is unable to participate in DCoA phosphorylation. We report that CTP actually inhibits the enzyme by decreasing its Vmax. Not surprisingly, a structural homology search for the modeled mycobacterial CoaE picks up cytidylmonophosphate kinases, deoxycytidine kinases, and cytidylate kinases as close homologs. Docking of DCoA and CTP to CoaE shows that both ligands bind at the same site, their interactions being stabilized by 26 and 28 hydrogen bonds respectively. We have also assigned a role for the universal Unknown Protein Family 0157 (UPF0157) domain in the mycobacterial CoaE in the proper folding of the full length enzyme.

Conclusions/significance

In view of the evidence presented, it is imperative to assign a greater role to the last enzyme of Coenzyme A biosynthesis in metabolite flow regulation through this critical biosynthetic pathway.

Seto A, Murayama K, Toyama M, Ebihara A, Nakagawa N, Kuramitsu S, Shirouzu M, Yokoyama S (2005)
ATP-induced structural change of dephosphocoenzyme A kinase from Thermus thermophilus HB8.
Proteins 58, 235-242 [PubMed:15526298]
[show Abstract]

Hoenke S, Wild MR, Dimroth P (2000)
Biosynthesis of triphosphoribosyl-dephospho-coenzyme A, the precursor of the prosthetic group of malonate decarboxylase.
Biochemistry 39, 13223-13232 [PubMed:11052675]
[show Abstract]

Izard T, Geerlof A (1999)
The crystal structure of a novel bacterial adenylyltransferase reveals half of sites reactivity.
The EMBO journal 18, 2021-2030 [PubMed:10205156]
[show Abstract]

Haugen HF, Skrede S (1976)
Nucleotide pyrophosphatase and phosphodiesterase I. Demonstration of activity in normal serum, and an increase in cholestatic liver disease.
Scandinavian journal of gastroenterology 11, 121-127 [PubMed:4880]
[show Abstract]

Last Modified

08 June 2021

CHEBI:15468 - 3'-dephospho-CoA

Background

Methodology/principal findings

Conclusions/significance

ChEBI is part of the ELIXIR infrastructure