Ewa Skrzypczak-Jankun

Lipoxygenase interactions with natural flavonoid, quercetin, reveal a complex with protocatechuic acid in its X-ray structure at 2.1 Å resolution

PUFA metabolites have a profound effect on inflammatory diseases and cancer progression. Blocking their production by inhibiting PUFA metabolizing enzymes (dioxygenases: cyclooxygenases and LOXs) might be a successful way to control and relieve such problems, if we learn to better understand their actions at a molecular level. Compounds with strong antioxidative and free radical scavenging properties, such as polyphenols, could be effective in blocking PUFA activities, and natural flavonoids possess such qualities. Quercetin belongs to the group of natural catecholic compounds and is known as a potent, competitive inhibitor of LOX. Structural analysis reveals that quercetin entrapped within LOX undergoes degradation, and the resulting compound has been identified by X‐ray analysis as protocatechuic acid (3,4‐dihydroxybenzoic acid) positioned near the iron site. Its C3‐OH group points toward His523, C4‐OH forms a hydrogen bond with OC from the enzymes C‐terminus, and the carboxylic group is incorporated into the hydrogen bonding network of the active‐site neighborhood via Gln514. This unexpected result, together with our previous observations concerning other polyphenols, yields new evidence about the metabolism of natural flavonoids. These compounds might be vulnerable to the co‐oxidase activity of LOX, leading to enzyme‐stimulated oxidative degradation, which results in an inhibitor of a lower molecular weight. Proteins 2004;54:000–000.

Soybean lipoxygenase-3 in complex with 4-nitrocatechol.

4-Nitrocatechol (4NC) is a known inhibitor of lipoxygenase. This work presents the X-ray structure of soybean lipoxygenase-3 in complex with 4NC refined at 2.15 A resolution. The X-ray analysis shows 4NC near iron with partial occupancy, blocking access to Fe but not covalently bound to it. The two hydroxyl groups interact with the C-terminus (4-OH) and His523 ND1 (3-OH). The residues surrounding the iron cofactor, His518*, His523, His709, Ile857* COO(-) and water, form a trigonal bipyramid with the residues marked with asterisks in the axial positions. The water bound to iron and the presence of the inhibitor seem to be responsible for the rearrangements and changes in the geometry of the ligand distribution and confirm the displacement of His518 from iron coordination. A description of the catechol binding contributes to the understanding of lipoxygenase inhibition and the participation of its co-oxidative activity in the utilization of natural flavonoids.

Control of the Aggressive Capacity of Prostate Cancer by Nutritional Inhibitors of Urokinase and Lipoxygenase

Abstract Pytochemicals of food and herbs are very potent antioxidants and free radical scavengers. It is accepted that these chemicals minimize DNA damage by reacting with free radicals and in this way they could prevent cancer. However, in some studies antioxidants increase incident of cancers instead of lowering it. These trials have caused a rethinking of the use of natural compounds as chemoprevention agents utilizing antioxidant concept. It was hypothesized instead that elements of food could react with enzymes crucial for cancer formation and growth. We choose two of these as an illustration of a concept. Urokinase and lipoxygenases are enzymes of a profound impact on cancer cells growth, metastasis and invasiveness. This article provides review of natural compounds, mostly antioxidants that are inhibitors of lipoxygenase and urokinase. Inhibition of these enzymes by food elements could prevent or reduce cancer growth in this way rather than utilizing antioxidant pathway.