The role of human tyrosinase (hTYR), an enzyme participating in the biosynthesis of melanin in the skin and neuromelanin in the brain, is still unclear. Elevated tyrosinase activity could trigger melanoma and PD. Our studies used different enzyme models to investigate the interaction between tyrosinase and inhibitors. We found that the bacterial tyrosinase (bTYR) and the most extensively used model, mushroom tyrosinase (mTYR), are not promising for the screening of genuine human tyrosinase inhibitors. Thus, it is important to optimize the methodology of human tyrosinase expression to produce the transmembrane protein for enzyme inhibition studies and crystallization studies.