Human lipoxygenase: developments in its structure, function, relevance to diseases and challenges in drug development

Area of Science:

• Biochemistry
• Enzymology
• Structural Biology

Background:

• Human lipoxygenases (LOXs) metabolize polyunsaturated fatty acids into eicosanoids, crucial for homeostasis.
• LOX enzymes are implicated in inflammatory responses, cancers, cardiovascular, kidney, and neurodegenerative diseases.

Purpose of the Study:

• To review recent structural data for human 12S-LOX and rabbit 15-LOX.
• To propose implications for the broader LOX enzyme family regarding structure, function, and drug development.

Main Methods:

• Analysis of available structural data for LOX and COX oxidoreductases.
• Review of recent developments in lipoxygenase research.

Main Results:

• Human lipoxygenases may function as oligomers of active and apo monomers.
• Sequential homodimers could form structural heterodimers via leucine zipper-like interactions.
• A third regulatory domain of alpha-beta character may explain LOX flexibility and signaling.

Conclusions:

• LOX molecular architecture likely involves more than two domains, offering drug development targets.
• Allosteric mechanisms may involve coordinated conformational changes and flexible linkers.
• Understanding LOX oligomerization and flexibility is key for therapeutic strategies.