Structural basis for the positional specificity of lipoxygenases.

Area of Science:

• Biochemistry
• Enzymology

Background:

• Mammalian lipoxygenases are classified by their positional specificity in arachidonic acid oxygenation.
• The structural basis for this specificity remains poorly understood.
• Direct structural data on lipoxygenase-substrate interactions are lacking.

Purpose of the Study:

• To review experimental data on the mechanistic reasons for lipoxygenase specificity.
• To explore models of enzyme-substrate interaction for arachidonic acid oxygenation.

Main Methods:

• Analysis of experiments with modified fatty acid substrates.
• Review of mutagenesis studies on lipoxygenases.
• Evaluation of existing models for enzyme-substrate interaction.

Main Results:

• For 12- and 15-lipoxygenases, arachidonic acid likely enters the substrate-binding pocket methyl-end first.
• Two models, orientation-determined and space-determined, exist for 5-lipoxygenation.
• Evidence suggests both models may apply to arachidonate 5-lipoxygenation depending on circumstances.

Conclusions:

• Lipoxygenase specificity is complex and influenced by substrate binding.
• Multiple mechanisms may govern arachidonic acid oxygenation by 5-lipoxygenases.
• Further research is needed to fully elucidate lipoxygenase-substrate interactions.