Inhibition of secreted phospholipase A2 by proanthocyanidins: A comparative enzymological and in silico modeling study

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Abstract

Secreted phospholipase A2 (PLA2) plays a critical role in mobilizing arachidonic acid in phospholipids. We have previously reported that PLA2 is inhibited by B-type proanthocyanidins (PaCs). To further understand the inhibitory activity of these compounds, we compared the inhibitory potency of B-type PaCs to that of A-type PaCs and modeled them with PLA2 using in silico techniques. The B-type trimer and tetramer inhibited PLA2 (IC50 = 16 and 10 μM). The A-type compounds were less potent (18-35% inhibition at 50 μM). The active site of PLA2 lies in a hydrophobic tunnel. Modeling studies revealed that the B-type PaCs occupy this tunnel and are stabilized by a number of van der Waals interactions. The result is reduced substrate access to the active site. The A-type compounds can occupy this tunnel only by shifting the N-terminal loop outward. Our data provide a structural basis to screen additional PaCs for anti-PLA2 activity.

Original languageEnglish (US)
Pages (from-to)7417-7420
Number of pages4
JournalJournal of Agricultural and Food Chemistry
Volume60
Issue number30
DOIs
StatePublished - Aug 1 2012

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Secretory Phospholipase A2
Proanthocyanidins
phospholipase A2
Phospholipases A2
proanthocyanidins
Computer Simulation
Tunnels
Catalytic Domain
active sites
Arachidonic Acid
Inhibitory Concentration 50
Phospholipids
arachidonic acid
inhibitory concentration 50
phospholipids
Substrates

All Science Journal Classification (ASJC) codes

  • Agricultural and Biological Sciences(all)
  • Chemistry(all)

Cite this

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title = "Inhibition of secreted phospholipase A2 by proanthocyanidins: A comparative enzymological and in silico modeling study",
abstract = "Secreted phospholipase A2 (PLA2) plays a critical role in mobilizing arachidonic acid in phospholipids. We have previously reported that PLA2 is inhibited by B-type proanthocyanidins (PaCs). To further understand the inhibitory activity of these compounds, we compared the inhibitory potency of B-type PaCs to that of A-type PaCs and modeled them with PLA2 using in silico techniques. The B-type trimer and tetramer inhibited PLA2 (IC50 = 16 and 10 μM). The A-type compounds were less potent (18-35{\%} inhibition at 50 μM). The active site of PLA2 lies in a hydrophobic tunnel. Modeling studies revealed that the B-type PaCs occupy this tunnel and are stabilized by a number of van der Waals interactions. The result is reduced substrate access to the active site. The A-type compounds can occupy this tunnel only by shifting the N-terminal loop outward. Our data provide a structural basis to screen additional PaCs for anti-PLA2 activity.",
author = "Lambert, {Joshua D.} and Neela Yennawar and Yeyi Gu and Ryan Elias",
year = "2012",
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TY - JOUR

T1 - Inhibition of secreted phospholipase A2 by proanthocyanidins

T2 - A comparative enzymological and in silico modeling study

AU - Lambert, Joshua D.

AU - Yennawar, Neela

AU - Gu, Yeyi

AU - Elias, Ryan

PY - 2012/8/1

Y1 - 2012/8/1

N2 - Secreted phospholipase A2 (PLA2) plays a critical role in mobilizing arachidonic acid in phospholipids. We have previously reported that PLA2 is inhibited by B-type proanthocyanidins (PaCs). To further understand the inhibitory activity of these compounds, we compared the inhibitory potency of B-type PaCs to that of A-type PaCs and modeled them with PLA2 using in silico techniques. The B-type trimer and tetramer inhibited PLA2 (IC50 = 16 and 10 μM). The A-type compounds were less potent (18-35% inhibition at 50 μM). The active site of PLA2 lies in a hydrophobic tunnel. Modeling studies revealed that the B-type PaCs occupy this tunnel and are stabilized by a number of van der Waals interactions. The result is reduced substrate access to the active site. The A-type compounds can occupy this tunnel only by shifting the N-terminal loop outward. Our data provide a structural basis to screen additional PaCs for anti-PLA2 activity.

AB - Secreted phospholipase A2 (PLA2) plays a critical role in mobilizing arachidonic acid in phospholipids. We have previously reported that PLA2 is inhibited by B-type proanthocyanidins (PaCs). To further understand the inhibitory activity of these compounds, we compared the inhibitory potency of B-type PaCs to that of A-type PaCs and modeled them with PLA2 using in silico techniques. The B-type trimer and tetramer inhibited PLA2 (IC50 = 16 and 10 μM). The A-type compounds were less potent (18-35% inhibition at 50 μM). The active site of PLA2 lies in a hydrophobic tunnel. Modeling studies revealed that the B-type PaCs occupy this tunnel and are stabilized by a number of van der Waals interactions. The result is reduced substrate access to the active site. The A-type compounds can occupy this tunnel only by shifting the N-terminal loop outward. Our data provide a structural basis to screen additional PaCs for anti-PLA2 activity.

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