PDBsum entry 1hnh

Transferase

PDB id

1hnh

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Contents

			Protein chain

					317 a.a. *

			Ligands

					COA

			Waters ×236

* Residue conservation analysis

PDB id:

1hnh

Links

Name:

Transferase

Title:

Crystal structure of beta-ketoacyl-acp synthase iii + degraded form of acetyl-coa

Structure:

Beta-ketoacyl-acyl carrier protein synthase iii. Chain: a. Synonym: 3-oxoacyl-[acyl-carrier-protein] synthase iii, beta- ketoacyl-acp synthase iii. Engineered: yes

Source:

Escherichia coli. Organism_taxid: 562. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Dimer (from PDB file)

Resolution:

1.90Å

R-factor:

0.221

R-free:

0.274

Authors:

X.Qiu,C.A.Janson,W.W.Smith,M.Head,J.Lonsdale,A.K.Konstantinidis

Key ref:

X.Qiu et al. (2001). Refined structures of beta-ketoacyl-acyl carrier protein synthase III. J Mol Biol, 307, 341-356. PubMed id: 11243824 DOI: 10.1006/jmbi.2000.4457

Date:

07-Dec-00

Release date:

27-Dec-00

PROCHECK

	Headers

	References

Protein chain

P0A6R0 (FABH_ECOLI) - Beta-ketoacyl-[acyl-carrier-protein] synthase III from Escherichia coli (strain K12)

Seq: Struc:					317 a.a. 317 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 1 residue position (black cross)



		Enzyme reactions

Enzyme class:

E.C.2.3.1.180 - beta-ketoacyl-[acyl-carrier-protein] synthase Iii.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

malonyl-[ACP] + acetyl-CoA + H⁺ = 3-oxobutanoyl-[ACP] + CO2 + CoA

malonyl-[ACP]

acetyl-CoA

H(+)

3-oxobutanoyl-[ACP]

CO2

CoA
Bound ligand (Het Group name = COA)
corresponds exactly

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1006/jmbi.2000.4457	J Mol Biol 307:341-356 (2001)
PubMed id: 11243824

Refined structures of beta-ketoacyl-acyl carrier protein synthase III.
X.Qiu, C.A.Janson, W.W.Smith, M.Head, J.Lonsdale, A.K.Konstantinidis.

ABSTRACT

beta-Ketoacyl-acyl carrier protein synthase III (FabH) is a condensing enzyme that plays central roles in fatty acid biosynthesis. Three-dimensional structures of E. coli FabH in the presence and absence of ligands have been refined to 1.46 A resolution. The structures of improved accuracy revealed detailed interactions involved in ligand binding. These structures also provided new insights into the FabH mechanism, e.g. the possible role of a water or hydroxyl anion in Cys112 deprotonation. A structure of the apo enzyme uncovered large conformational changes in the active site, exemplified by the disordering of four essential loops (84-86, 146-152, 185-217 and 305-307) and the movement of catalytic residues (Cys112 and His244). The disordering of the loops leads to greater than 50 % reduction in the FabH dimer interface, suggesting a dynamic nature for an unusually large portion of the dimer interface. The existence of a large solvent-accessible channel in the dimer interface as well as two cis-peptides (cis-Pro88 and cis-Phe308) in two of the disordered loops may explain the observed structural instabilities.

Selected figure(s)



	Figure 3. Figure 3. Electron density for Cys112 and a bound phosphate ion in the O-FabH Structure. (a) The SA-omit map at Cys112, contoured at 1.5 s. The extra density, centered at 2.3 Å from the Sg atom, could be a tightly bound water molecule or hydroxyl anion (OH -). (b) The density for a bound phosphate ion, also contoured at 1.5 s. Broken lines indicate the hydrogen bonds (distances labeled) between the phosphate ion and FabH.		Figure 4. Figure 4. The CoA binding mode observed in the FabH+CoA structure. (a) The electron density for the bound CoA molecule contoured at 1.0 s. Atoms are colored in the same way as in previous figures. (b) Stereoview of the CoA molecule in the FabH active site tunnel. Amino acid residues are labeled and hydrogen bonds are shown with broken lines. CoA is drawn in thicker lines with the carbon atoms in purple. (c) Stereoview of Arg42 and its role in stabilizing helices La5 and La2. Hydrogen bonding interactions are shown in red dashed lines. The adenine of CoA is shown with magenta bonds.

Figures were selected by an automated process.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21516317

Y.Pérez-Castillo, M.Froeyen, M.A.Cabrera-Pérez, and A.Nowé (2011).
Molecular dynamics and docking simulations as a proof of high flexibility in E. coli FabH and its relevance for accurate inhibitor modeling.

J Comput Aided Mol Des, 25, 371-393.

20221630

D.González-Mellado, P.von Wettstein-Knowles, R.Garcés, and E.Martínez-Force (2010).
The role of beta-ketoacyl-acyl carrier protein synthase III in the condensation steps of fatty acid biosynthesis in sunflower.

Planta, 231, 1277-1289.

20534558

E.Okamura, T.Tomita, R.Sawa, M.Nishiyama, and T.Kuzuyama (2010).
Unprecedented acetoacetyl-coenzyme A synthesizing enzyme of the thiolase superfamily involved in the mevalonate pathway.

Proc Natl Acad Sci U S A, 107, 11265-11270.

19694421

A.K.Bera, V.Atanasova, H.Robinson, E.Eisenstein, J.P.Coleman, E.C.Pesci, and J.F.Parsons (2009).
Structure of PqsD, a Pseudomonas quinolone signal biosynthetic enzyme, in complex with anthranilate.

Biochemistry, 48, 8644-8655.

PDB codes:

3h76 3h77 3h78

19074144

R.Veyron-Churlet, V.Molle, R.C.Taylor, A.K.Brown, G.S.Besra, I.Zanella-Cléon, K.Fütterer, and L.Kremer (2009).
The Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III activity is inhibited by phosphorylation on a single threonine residue.

J Biol Chem, 284, 6414-6424.

18453702

B.Bagautdinov, Y.Ukita, M.Miyano, and N.Kunishima (2008).
Structure of 3-oxoacyl-(acyl-carrier protein) synthase II from Thermus thermophilus HB8.

Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 358-366.

PDB code:

1j3n

19022176

G.Castaldo, J.Zucko, S.Heidelberger, D.Vujaklija, D.Hranueli, J.Cullum, P.Wattana-Amorn, M.P.Crump, J.Crosby, and P.F.Long (2008).
Proposed arrangement of proteins forming a bacterial type II polyketide synthase.

Chem Biol, 15, 1156-1165.

18096200

S.Sachdeva, F.Musayev, M.M.Alhamadsheh, J.Neel Scarsdale, H.Tonie Wright, and K.A.Reynolds (2008).
Probing reactivity and substrate specificity of both subunits of the dimeric Mycobacterium tuberculosis FabH using alkyl-CoA disulfide inhibitors and acyl-CoA substrates.

Bioorg Chem, 36, 85-90.

PDB code:

2qx1

17707686

H.T.Wright, and K.A.Reynolds (2007).
Antibacterial targets in fatty acid biosynthesis.

Curr Opin Microbiol, 10, 447-453.

17524982

M.M.Alhamadsheh, F.Musayev, A.A.Komissarov, S.Sachdeva, H.T.Wright, N.Scarsdale, G.Florova, and K.A.Reynolds (2007).
Alkyl-CoA disulfides as inhibitors and mechanistic probes for FabH enzymes.

Chem Biol, 14, 513-524.

PDB codes:

2eft 2gyo

16356722

A.M.Haapalainen, G.Meriläinen, and R.K.Wierenga (2006).
The thiolase superfamily: condensing enzymes with diverse reaction specificities.

Trends Biochem Sci, 31, 64-71.

16717405

H.Yoneyama, and R.Katsumata (2006).
Antibiotic resistance in bacteria and its future for novel antibiotic development.

Biosci Biotechnol Biochem, 70, 1060-1075.

16618705

Y.M.Zhang, J.Hurlbert, S.W.White, and C.O.Rock (2006).
Roles of the active site water, histidine 303, and phenylalanine 396 in the catalytic mechanism of the elongation condensing enzyme of Streptococcus pneumoniae.

J Biol Chem, 281, 17390-17399.

PDB code:

2alm

15952903

S.W.White, J.Zheng, Y.M.Zhang, and Rock (2005).
The structural biology of type II fatty acid biosynthesis.

Annu Rev Biochem, 74, 791-831.

15987898

X.Qiu, A.E.Choudhry, C.A.Janson, M.Grooms, R.A.Daines, J.T.Lonsdale, and S.S.Khandekar (2005).
Crystal structure and substrate specificity of the beta-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus.

Protein Sci, 14, 2087-2094.

PDB code:

1zow

15016358

A.C.Price, Y.M.Zhang, C.O.Rock, and S.W.White (2004).
Cofactor-induced conformational rearrangements establish a catalytically competent active site and a proton relay conduit in FabG.

Structure, 12, 417-428.

PDB codes:

1q7b 1q7c

14766582

C.T.Nomura, K.Taguchi, S.Taguchi, and Y.Doi (2004).
Coexpression of genetically engineered 3-ketoacyl-ACP synthase III (fabH) and polyhydroxyalkanoate synthase (phaC) genes leads to short-chain-length-medium-chain-length polyhydroxyalkanoate copolymer production from glucose in Escherichia coli JM109.

Appl Environ Microbiol, 70, 999.

15265863

M.B.Austin, M.Izumikawa, M.E.Bowman, D.W.Udwary, J.L.Ferrer, B.S.Moore, and J.P.Noel (2004).
Crystal structure of a bacterial type III polyketide synthase and enzymatic control of reactive polyketide intermediates.

J Biol Chem, 279, 45162-45174.

PDB code:

1u0m

14660674

R.Yasuno, P.von Wettstein-Knowles, and H.Wada (2004).
Identification and molecular characterization of the beta-ketoacyl-[acyl carrier protein] synthase component of the Arabidopsis mitochondrial fatty acid synthase.

J Biol Chem, 279, 8242-8251.

15273125

X.He, A.M.Reeve, U.R.Desai, G.E.Kellogg, and K.A.Reynolds (2004).
1,2-dithiole-3-ones as potent inhibitors of the bacterial 3-ketoacyl acyl carrier protein synthase III (FabH).

Antimicrob Agents Chemother, 48, 3093-3102.

15052334

Y.J.Lu, Y.M.Zhang, and C.O.Rock (2004).
Product diversity and regulation of type II fatty acid synthases.

Biochem Cell Biol, 82, 145-155.

12837788

A.C.Price, C.O.Rock, and S.W.White (2003).
The 1.3-Angstrom-resolution crystal structure of beta-ketoacyl-acyl carrier protein synthase II from Streptococcus pneumoniae.

J Bacteriol, 185, 4136-4143.

PDB codes:

1ox0 1oxh

12429097

H.Pan, S.Tsai, E.S.Meadows, L.J.Miercke, A.T.Keatinge-Clay, J.O'Connell, C.Khosla, and R.M.Stroud (2002).
Crystal structure of the priming beta-ketosynthase from the R1128 polyketide biosynthetic pathway.

Structure, 10, 1559-1568.

PDB code:

1mzj

11959561

X.He, and K.A.Reynolds (2002).
Purification, characterization, and identification of novel inhibitors of the beta-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus.

Antimicrob Agents Chemother, 46, 1310-1318.

11369293

D.J.Payne, P.V.Warren, D.J.Holmes, Y.Ji, and J.T.Lonsdale (2001).
Bacterial fatty-acid biosynthesis: a genomics-driven target for antibacterial drug discovery.

Drug Discov Today, 6, 537-544.

11728875

D.McDevitt, and M.Rosenberg (2001).
Exploiting genomics to discover new antibiotics.

Trends Microbiol, 9, 611-617.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.