Substrates in the cell are often at concentrations in the Km range. Slight changes in the enzymes Km, caused by allosteric ligands, can cause dramatic changes in the amount of product produced. Reactions that are intrinsically energetically unfavorable must be coupled to energetically favorable reactions. ATP hydrolysis releases a lot of energy. ATP hydrolysis is often used to make unfavorable reactions favorable.
Some enzymes form covalent intermediates with their substrates.
Often the product of one metabolic reaction is the substrate for another. The need for a product of one reaction to diffuse to the second enzyme can slow the reaction down. Some enzymes reside in large complexes, where the product of one reaction is directly 'handed off' to the active site of the second reaction.