Proteolytic activity of the Cu(II) complex of 1-oxa-4,7,10-triazacyclododecane (oxacyclen) was compared with that of the Cu(II) complex of 1,4,7,10-tetraazacyclododecane by using albumin, gamma-globulin, and myoglobin as substrates. Values of kcat/Km were greater for Cu(II)oxacyclen by 40-80 times. The enhanced activity is attributed to the increased Lewis acidity of Cu(II) due to substitution of one nitrogen donor atom with oxygen.