Lipoxygenase

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Arachidonate 15-Lipoxygenase
Identifiers
Symbol	Lipoxygenase
Pfam	PF00305
InterPro	IPR013819
SCOP	2sbl
OPM family	87
OPM protein	1zq4
Available PDB structures: 1y4kA: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

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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^[1]. In mammals a number of lipoxygenases isozymes are involved in the metabolism of prostaglandins and leukotrienes^[1]. Sequence data is available for the following lipoxygenases:

• Plant lipoxygenases (EC 1.13.11.12InterPro IPR001246). Plants express a variety of cytosolic isozymes as well as what seems to be a chloroplast isozyme^[1].
• Mammalian arachidonate 5-lipoxygenase (EC 1.13.11.34InterPro IPR001885).
• Mammalian arachidonate 12-lipoxygenase (EC 1.13.11.31InterPro IPR001885).
• Mammalian erythroid cell-specific 15-lipoxygenase (EC 1.13.11.33InterPro IPR001885).

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^[1]. 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^[1] 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 N^ε 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 N^δ atom. Thus, the coordination number of iron is either five or six, with a hydroxyl or water ligand to a hexacoordinate iron.

Biochemical classification

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. Tejero, I.; Eriksson, L. A.; Gonzalez-Lafont, A.; Marquet, J.; Lluch, J. M. Hydrogen Abstraction by Soybean Lipoxygenase-1. Density Functional Theory Study on Active Site Models in Terms of Gibbs Free Energies [2]J. Phys. Chem. B, 2004,108, 13831

• Kulkarni, A.P. (2001). "Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and xenobiotics". Cell Mol Life Sci 58: 1805–1825. PMID 11766881..
• Nelson, M.J. and Seitz, S.P. (1994). "The structure and function of lipoxygenase". Curr Opin Struct Biol 4: 878–884. PMID 8161558..

External links

• LOX-DB - LipOXygenases DataBase
• PDB 1YGE - structure of lipoxygenase-1 from soybean (Glycine max)
• PDB 1IK3 - structure of soybean lipoxygenase-3 in complex with (9Z,11E,13S)-13-hydroperoxyoctadeca-9,11-dienoic acid
• PDB 1LOX - structure of rabbit 15-lipoxygenase in complex with inhibitor
• UMich Orientation of Proteins in Membranes families/superfamily-87 - animal lipoxygenases
• MeSH Lipoxygenase

This article includes text from the public domain Pfam and InterPro IPR001024

de:Lipoxygenase

Acknowledgement and Attribution Regarding Sources of Content

Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .