As shown in Scheme 1, the catalytic cycle of LiP involves three main stages. Similar to other peroxidases, the first stage (I) involves the activation by H2O2 to form a ferryl ion porphyrin π-cation radical species (Cpd I), a common active species in peroxidases. In the second stage (II), Cpd-I performs one-electron oxidation of the lignin substrate, yielding Cpd II and the lignin cation radical species (S •+ ). Emerging from this lignin cation radical species, C-C or C-O cleavage can occur to generate the lignin fragments. In the third stage (III), Cpd II can perform a second-round oxidation of the lignin substrate, returning the enzyme to the native ferric state. Currently, it is widely accepted that the oxidation of lignin by Cpd I/II involves a long-range ET from the lignin substrate to Cpd I/II. Such long-range ET could be mediated by some redox-active residues exposed at the protein surface. In both VP and LiP, a tryptophan radical (Trp171 in LiP and Trp164 in VP) has been characterized by EPR spectroscopy, suggesting that the oxidation of lignin may occur via two long-range ET steps mediated by Trp (see Figure ). One involves ET from Trp171 to Cpd I, while the other involves ET from the lignin substrate to the Trp171 radical. However, it is still unclear how the Trp radical is formed and how can it modulate the two ET steps. In addition to the unsolved electron transfer mechanism in LiP, a long-standing issue exists for the pH-dependent reactivity of LiP. Specifically, it was found that both the ET rates for Cpd I→Cpd II (stage II in Scheme 1) and Cpd II→Resting Fe(III) state (stage III in Scheme 1) can be enhanced by ~10 3 folds from pH=7 to the optimal pH=3. To rationalize this puzzle, various explanations have been proposed. For instance, early studies suggested that low pH may be helpful to stabilize the lignin cation radical. However, low pH would lead to a more positively charged protein environment, which may destabilize the substrate cation radical through electrostatic repulsion. In addition, it was proposed that low pH can protonate the titratable residues close to Heme, which may elevate the redox potential of Cpd I, thereby increasing the oxidizing power of Cpd I towards lignin oxidation. However, the increase of redox potential for Cpd I can only increase the driving force for the first ET step (Trp171→Cpd I), while the thermodynamics of the second ET step (lignin→Trp171) are unlikely be affected.