Experimental and Computational Study to Reveal the Potential of Non-Polar Constituents from Hizikia fusiformis as Dual Protein Tyrosine Phosphatase 1B and α-Glucosidase Inhibitors

Abstract

<i>Hizikia fusiformis</i> (Harvey) Okamura is an edible marine alga that has been widely used in Korea, China, and Japan as a rich source of dietary fiber and essential minerals. In our previous study, we observed that the methanol extract of <i>H. fusiformis</i> and its non-polar fractions showed potent protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase inhibition. Therefore, the aim of the present study was to identify the active ingredient in the methanol extract of <i>H. fusiformis</i>. We isolated a new glycerol fatty acid (<b>13</b>) and 20 known compounds including 9 fatty acids (<b>1</b>-<b>3</b>, <b>7</b>-<b>12</b>), mixture of 24<i>R</i> and 24<i>S</i>-saringosterol (<b>4</b>), fucosterol (<b>5</b>), mixture of 24<i>R</i>,28<i>R</i> and 24<i>S</i>,28<i>R</i>-epoxy-24-ethylcholesterol (<b>6</b>), cedrusin (<b>14</b>), 1-(4-hydroxy-3-methoxyphenyl)-2-[2-hydroxy -4-(3-hydroxypropyl)phenoxy]-1,3-propanediol (<b>15</b>), benzyl alcohol alloside (<b>16</b>), madhusic acid A (<b>17</b>), glycyrrhizin (<b>18</b>), glycyrrhizin-6'-methyl ester (<b>19</b>), apo-9'-fucoxanthinone (<b>20</b>) and tyramine (<b>21</b>) from the non-polar fraction of <i>H. fusiformis</i>. New glycerol fatty acid <b>13</b> was identified as 2-(7'- (2″-hydroxy-3″-((5<i>Z</i>,8<i>Z</i>,11<i>Z</i>)-icosatrienoyloxy)propoxy)-7'-oxoheptanoyl)oxymethylpropenoic acid by spectroscopic analysis using NMR, IR, and HR-ESI-MS. We investigated the effect of the 21 isolated compounds and metabolites (<b>22</b> and <b>23</b>) of <b>18</b> against the inhibition of PTP1B and α-glucosidase enzymes. All fatty acids showed potent PTP1B inhibition at low concentrations. In particular, new compound <b>13</b> and fucosterol epoxide (<b>6</b>) showed noncompetitive inhibitory activity against PTP1B. Metabolites of glycyrrhizin, <b>22</b> and <b>23</b>, exhibited competitive inhibition against PTP1B. These findings suggest that <i>H. fusiformis</i>, a widely consumed seafood, may be effective as a dietary supplement for the management of diabetes through the inhibition of PTP1B.