We use the first systematic samples of CO millimeter emission in z>1 main-sequence star forming galaxies (SFGs) to study the metallicity dependence of the conversion factor {alpha}CO, from CO line luminosity to molecular gas mass. The molecular gas depletion rate inferred from the ratio of the star formation rate (SFR) to CO luminosity, is ~1 Gyr-1 for near-solar metallicity galaxies with stellar masses above M_S~1e11 M_sun. In this regime the depletion rate does not vary more than a factor of two to three as a function of molecular gas surface density, or redshift between z~0 and 2. Below M_S the depletion rate increases rapidly with decreasing metallicity. We argue that this trend is not caused by starburst events, by changes in the physical parameters of the molecular clouds, or by the impact of the fundamental metallicity-SFR-stellar mass relation. A more probable explanation is that the conversion factor is metallicity dependent and that star formation can occur in CO-dark gas. The trend is also expected theoretically from the effect of enhanced photodissociation of CO by ultraviolet radiation at low metallicity. From the available z~0 and z~1-3 samples we constrain the slope of the log({alpha}CO) -log (metallicity) relation to range between -1 and -2, fairly insensitive to the assumed slope of the gas-star formation rate relation. Because of the lower metallicities near the peak of the galaxy formation activity at z~1-2 compared to z~0, we suggest that molecular gas masses estimated from CO luminosities have to be substantially corrected upward for galaxies below M_S.
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