Identification and Total Synthesis of Two Previously Unreported Odd-Chain Bis-Methylene-Interrupted Fatty Acids with a Terminal Olefin that Activate Protein Phosphatase, Mg2+/Mn2+-Dependent 1A (PPM1A) in Ovaries of the Limpet Cellana toreuma

Abstract

Diverse non-methylene-interrupted (NMI) fatty acids (FAs) with odd-chain lengths have been recognized in triacylglycerols and polar lipids from the ovaries of the limpet Cellana toreuma, however their biological properties remain unclear. In this study, two previously unreported odd-chain NMI FAs, (12Z)-12,16-heptadecadienoic (1) and (14Z)-14,18-nonadecadienoic (2) acids, from the ovary lipids of C. toreuma were identified by a combination of equivalent chain length (ECL) values of their methyl esters and capillary gas chromatography-mass spectrometry (GC-MS) of their 3-pyridylcarbinol derivatives. On the basis of the experimental results, both 1 and 2 were synthesized to prove their structural assignments and to test their biological activity. The ECL values and electron impact-mass (EI-MS) spectra of naturally occurring 1 and 2 were in agreement with those of the synthesized 1 and 2. In an in vitro assay, both 1 and 2 activated protein phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A) up to 100 μM in a dose-dependent manner.

Novel Non‐methylene‐Interrupted Dienoic and Trienoic Fatty Acids with a Terminal Double Bond in Ovaries of the Limpet Cellana toreuma

“…Although long‐chain dienoic and trienoic NMI FA are frequently present in marine mollusks and sponges, their role and function remain largely unknown. Among highly diverse NMI FA occurring in the gonads of the limpets C. grata and C. toreuma are (12 Z )‐12,16‐heptadecadienoic acid (17:2Δ12 Z ,14), (14 Z )‐14,18‐nonadecadienoic acid (19:2Δ14 Z ,18), and (9 Z ,20 Z )‐9,20‐tricosadienoic acid (23:2Δ9 Z ,20 Z ) activated protein phosphatase M1A (PPM1A), formally called protein phosphatase 2Cα (Kawashima et al, ), while 23:2Δ9 Z ,20 Z also displayed inhibitory activity against glycogen synthase kinase‐3β (GSK‐3β) and cytotoxicity against HL60 cells (Yoshida et al, ). Moreover, (4 Z ,15 Z )‐4,15‐octadecadienoic acid (18:2Δ4 Z ,15 Z ) with inhibitory activity against GSK‐3β, which is a chain‐elongation analogue of 23:2Δ9 Z ,20 Z , was found to inhibit glucose production in rat hepatoma H4IIE cells (Yoshida et al, ).…”

“…The same total lipids extracted from ovaries of the limpet C. toreuma , which were collected on 5 and 25 August 2016 in Otsuchi Bay, Iwate, northeastern Japan, described previously (Kawashima et al, ) were used in this study.…”

“…Recently, ovaries of the limpets Cellana grata and Cellana toreuma , belonging to archaeogastropods, have been proved to be a rich source of structurally diverse NMI FA, including dienoic FA with a terminal double bond, dienoic FA with a 5,9‐double bond, and dienoic FA with a 9,15‐double bond (Kawashima, , ; Kawashima et al, ; Kawashima and Ohnishi, , , , ). In addition, previous work with odd‐chain NMI FA regioisomers in limpet gonads has resulted in the discovery of biological active compounds as novel protein phosphatase M1A (PPM1A) activators and glycogen synthase kinase‐3β (GSK‐3β) inhibitors (Kawashima et al, : Yoshida et al, ). However, the biological properties of uncommon NMI FA in cells are yet to be investigated.…”

Recent advances on marine mollusk-derived natural products: chemistry, chemical ecology and therapeutical potential

“…Diverse non-methine-interrupted (NMI) FAs with odd-chain lengths have been recognized in triacylglycerols and polar lipids from the ovaries of the limpet Cellana toreuma but their biological properties remain unclear. Two odd-chain NMI FAs, (12 Z )-12,16-heptadecadienoic ( 368 ) and (14 Z )-14,18-nonadecadienoic ( 369 ), were identified from the ovary lipids of the Patellogastropoda Cellana toreuma (Otsuchi Bay, Iwate, Japan) by Kawashima et al , 276 using a combination of equivalent chain length (ECL) values of their methyl esters and capillary GC-MS of their 3-pyridylcarbinol derivatives. Then, both 368 and 369 were synthesized to prove their structural assignments and to test their biological activity.…”