Single amino acid substitutions in the lactose permease of Escherichia coli are known to elicit behaviour, such as the transformation of an active into a passive system, not explained by current co-transport models. The behaviour, it is shown, can be explained by an expanded reaction scheme that takes account of the required alternation of the carrier, in the course of the coupled reaction, between mobile and immobile conformations or between conformations that bind either only one substrate or both substrates. The extended model links such behaviour to altered conformational equilibria or binding regions. Thus, mutations that affect the equilibrium between a mobile one-site conformation of the free carrier and an immobile conformation having sites for both substrates allow passive transport of the second substrate in an ordered mechanism, and mutations in a secondary substrate binding region that affects this conformational change allow passive transport of the first substrate. Mutations in regions interacting with a substrate in the transition state in carrier movement, as well as in the initial binding sites, can also be distinguished. The analysis applies to both primary and secondary active transport.