Lipoxygenase

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Lipoxygenases are iron-containing enzymes that catalyse the dioxygenation of polyunsaturated fatty acids in reaction:

fatty acid + O₂ = fatty acid hydroperoxide

Lipoxygenases are found in plants and in animals. Products of plant and animal lipoxygenases are involved in diverse cell functions.

Contents 1 Biochemical classification 2 5-lipoxygenase (5LO) 3 Structure 4 References 5 External links

[edit] 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.

[edit] 5-lipoxygenase (5LO)

5-lipoxygenase (5-LO or Alox5), which transforms EFAs into leukotrienes, is a current target for pharmaceutical intervention in a number of diseases. EFA substrates and leukotriene products of 5-LO include:

• Arachidonic acid (AA) yields the 4-series leukotrienes (LTB4, LTC4, LTD4, LTE4 — generally proinflammatory)
• Eicosapentaenoic acid (EPA) yields the 5-series (LTB5, LTC5, LTD5, LTE5 — antiinflammatory)
• Gamma-linolenic acid (GLA via the DGLA intermediary) yields no leukotrienes, but inhibits the conversion of AA.

5-LO catalyzes oxidation of AA at the 5-position to yield 5-hydroperoxyeicosatetraenoic acid (5-HPETE). Two other lipoxygenases, 12-LO and 15-LO, act at the 12- and 15-positions, yielding 12- and 15-HPETE. These pathways lead to the leukotriene 12-hydroxyeicosatetraenoic acid (12-HETE) and to the lipoxins, respectively.^[1]

5-LO is a target for pharmaceutical intervention in CAD.^[2] Some people with variant alleles for 5-LO are at elevated risk for CAD.^[3] 5-LO is expressed in brain cells and may participate in neuropathologic processes [4]. As leukotrienes are important causes of pathological symptoms in asthma, 5-LO inhibitors were developed as asthma treatments. The only 5-LO inhibitor currently licensed for human use in asthma is Zileuton.

5-LO is activated by 5-lipoxygenase activating protein (FLAP).

[edit] Structure

The crystal structures of soybean and rabbit lipoxygenases are known. The protein consists of a small N-terminal domain and a major C-terminal domain, 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. It has been noted that the β-barrel domain of mammalian lipoxygenase is more similar in sequence, size and structure to an analogous C-terminal β-barrel domain in the mammalian lipases than to the homologous domain in plant lipoxygenases. 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. 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.

[edit] References

1. ↑  UCLA, 5-Lipoxygenase, A New Therapeutic And Diagnostic Target For Heart Disease Management UCLA Case No. 2001-429 PCT Publication Number: WO 03/035670 A2 [5] URL referenced 10/25/05.
2. ↑  JH Dwyer et al Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med. 2004 Jan 1;350(1):4-7. [6]
3. ↑  Dorlands Medical Dictionary, entries at arachidonate 5-lipoxygenase and following. URL referenced 7 February 2006.
4. 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 [7]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. .

[edit] 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 - Spatial positions of animal lipoxygenases in membranes
• MeSH Lipoxygenase