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Lipoxygenase

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This is an old revision of this page, as edited by JustAnotherKinase (talk | contribs) at 08:13, 22 August 2010 (Inserted the more comprehensive term "eicosanoid" before the terms leukotriene & prostaglandin & the term "nonclassic eicosanoids"). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Lipoxygenase
Structure of rabbit reticulocyte 15S-lipoxygenase.[1]
Identifiers
SymbolLipoxygenase
PfamPF00305
InterProIPR013819
PROSITEPDOC00077
SCOP22sbl / SCOPe / SUPFAM
OPM superfamily87
OPM protein1zq4
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1y4kA:155-823 2sblB:155-823 1fgoA:155-823

1fgmA:155-823 1yge :155-823 1fgtA:155-823 1f8nA:155-823 1fgqA:155-823 1fgrA:155-823 1rrhA:173-841 1rovA:173-841 1lnh :173-841 1no3A:173-841 1n8qA:173-841 1rrlB:173-841 1hu9A:173-841 1ik3A:173-841 1jnqA:173-841

1lox :122-655 1zq4A:498-1058

Lipoxygenases (EC 1.13.11.-) are a family of iron-containing enzymes that catalyse the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene structure. It catalyses the following reaction:

fatty acid + O2 = fatty acid hydroperoxide

Lipoxygenases are found in plants, animals and fungi. Products of lipoxygenases are involved in diverse cell functions.

Biological function and classification

These enzymes are most common in plants where they may be involved in a number of diverse aspects of plant physiology including growth and development, pest resistance, and senescence or responses to wounding[2]. In mammals a number of lipoxygenases isozymes are involved in the metabolism of eicosanoids (such as prostaglandins, leukotrienes and nonclassic eicosanoids)[3]. Sequence data is available for the following lipoxygenases:

Rabbit 15-lipoxygenase (blue) with inhibitor (yellow) bound in the active site

3D structure

The crystal structures of soybean and rabbit lipoxygenases are known. The protein consists of a small N-terminal PLAT domain and a major C-terminal catalytic domain (see Pfam link in this article), which contains the active site. In both plant and mammalian enzymes, the N-terminal domain contains an eight-stranded antiparallel β-barrel, but in the soybean lipoxygenases this domain is significantly larger than in the rabbit enzyme. The plant lipoxygenases can be enzymatically cleaved into two fragments which stay tightly associated while the enzyme remains active; separation of the two domains leads to loss of catalytic activity. The C-terminal (catalytic) domain consists of 18-22 helices and one (in rabbit enzyme) or two (in soybean enzymes) antiparallel β-sheets at the opposite end from the N-terminal β-barrel.

Active site

The iron atom in lipoxygenases is bound by four ligands, three of which are histidine residues[5]. Six histidines are conserved in all lipoxygenase sequences, five of them are found clustered in a stretch of 40 amino acids. This region contains two of the three zinc-ligands; the other histidines have been shown[6] to be important for the activity of lipoxygenases.

The two long central helices cross at the active site; both helices include internal stretches of π-helix that provide three histidine (His) ligands to the active site iron. Two cavities in the major domain of soybean lipoxygenase-1 (cavities I and II) extend from the surface to the active site. The funnel-shaped cavity I may function as a dioxygen channel; the long narrow cavity II is presumably a substrate pocket. The more compact mammalian enzyme contains only one boot-shaped cavity (cavity II). In soybean lipoxygenase-3 there is a third cavity which runs from the iron site to the interface of the β-barrel and catalytic domains. Cavity III, the iron site and cavity II form a continuous passage throughout the protein molecule.

The active site iron is coordinated by Nε of three conserved His residues and one oxygen of the C-terminal carboxyl group. In addition, in soybean enzymes the side chain oxygen of asparagine is weakly associated with the iron. In rabbit lipoxygenase, this Asn residue is replaced with His which coordinates the iron via Nδ atom. Thus, the coordination number of iron is either five or six, with a hydroxyl or water ligand to a hexacoordinate iron.

Biochemical classification

EC 1.13.11.12 lipoxygenase (linoleate:oxygen 13-oxidoreductase) linoleate + O2 = (9Z,11E,13S)-13-hydroperoxyoctadeca-9,11-dienoate
EC 1.13.11.31 arachidonate 12-lipoxygenase (arachidonate:oxygen 12-oxidoreductase) arachidonate + O2 = (5Z,8Z,10E,12S,14Z)-12-hydroperoxyicosa-5,8,10,14-tetraenoate
EC 1.13.11.33 arachidonate 15-lipoxygenase (arachidonate:oxygen 15-oxidoreductase) arachidonate + O2 = (5Z,8Z,11Z,13E,15S)-15-hydroperoxyicosa-5,8,11,13-tetraenoate
EC 1.13.11.34 arachidonate 5-lipoxygenase (arachidonate:oxygen 5-oxidoreductase) arachidonate + O2 = leukotriene A4 + H2
EC 1.13.11.40 arachidonate 8-lipoxygenase (arachidonate:oxygen 8-oxidoreductase) arachidonate + O2 = (5Z,8R,9E,11Z,14Z)-8-hydroperoxyicosa-5,9,11,14-tetraenoate

Soybean Lipoxygenase 1 exhibits the largest H/D kinetic isotope effect (KIE) on kcat (kH/kD) (81 near room temperature) so far reported for a biological system.

References

  1. ^ Choi J, Chon JK, Kim S, Shin W (2008). "Conformational flexibility in mammalian 15S-lipoxygenase: Reinterpretation of the crystallographic data". Proteins. 70 (3): 1023–32. doi:10.1002/prot.21590. PMID 17847087. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Vick BA, Zimmerman DC (1987). "Oxidative systems for the modification of fatty acids". 9: 53–90. {{cite journal}}: Cite journal requires |journal= (help)
  3. ^ Needleman P, Turk J, Jakschik BA, Morrison AR, Lefkowith JB (1986). "Arachidonic acid metabolism". Annu. Rev. Biochem. 55: 69–102. doi:10.1146/annurev.bi.55.070186.000441. PMID 3017195.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Tanaka K, Ohta H, Peng YL, Shirano Y, Hibino T, Shibata D (1994). "A novel lipoxygenase from rice. Primary structure and specific expression upon incompatible infection with rice blast fungus". J. Biol. Chem. 269 (5): 3755–3761. PMID 7508918. {{cite journal}}: line feed character in |author= at position 15 (help)CS1 maint: multiple names: authors list (link)
  5. ^ Boyington JC, Gaffney BJ, Amzel LM (1993). "The three-dimensional structure of an arachidonic acid 15-lipoxygenase". Science. 260 (5113): 1482–1486. doi:10.1126/science.8502991. PMID 8502991.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Steczko J, Donoho GP, Clemens JC, Dixon JE, Axelrod B (1992). "Conserved histidine residues in soybean lipoxygenase: functional consequences of their replacement". Biochemistry. 31 (16): 4053–4057. doi:10.1021/bi00131a022. PMID 1567851.{{cite journal}}: CS1 maint: multiple names: authors list (link)
This article incorporates text from the public domain Pfam and InterPro: IPR001024
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