Abstract The initial step in the B 12-dependent isomerase and ribonucleotide reductase enzymes involves the reversible homolytic fission of the CoC bond in the B 12 coenzyme to give Co 2 and the free radical R· according to (1); for recent reviews see  and, in particular, . Since the CoC bond of organocorrinoids is normally very stable at physiological pH in the dark, one of the main roles of the protein is to labilise this bond [2, 3]. The use of synthetic analogues has shown [4, 5]. that none of the oxygen atoms in the ribose part of the organo-ligand of coenzyme are essential for enzymatic activity, although the adenine part is probably essential for binding to the protein, i.e. the ligand can be considered as a simple alkyl ligand. Studies of the effect of increasing steric compression around the coordinated C atom of alkyl-corrinoids (due to increasing the degree of substitution on the α or β atoms or the size of the alicylic ring) on the rate of CoC bond fission, the coordination of ligands in the trans-position and the spectra of the alkyl-corrinoids (data summarized in ref. ), as well as the structures of the cobaloximes [RCo-(DH) 2py] with R = Me , Et , Pr i  and neopentyl , have revealed a simple pattern of steric interactions . The main results of interest here are that increasing steric compression labilises the CoC bond (by > 10 7 on changing from R = Me to CHEt 2) and will convert the normal red six-coordinate form with its first adsorption band at ∼440 nm. Several B 12-dependent enzymes do, in fact, show a hitherto unexplained band at ∼440 nm, but only during the enzyme-substrate steady-state [10-13]. This can now fairly confidently be identified as a distorted five-coordinte yellow form of the co-enzyme (CoR *), which is formed (see expanded scheme (2)) from the normal six-coordinate red form (BCoR) as the substrate (SH) binds (and presumably induces a change in protein conformation P to P 1) and which forms a labile equilibrium with Co 2 and R· . Values of k r ∼ 2 × 10 9 M −1 s −1 have been obtained [14, 15] by picosecond flash photolysis for methylcobalamin methylcobalamin and the coenzyme, which are close to the diffusion-controlled limit. Since the equilibrium constant for reaction 910, K eq = K f/k r, there is no scope for the protein to labilise the CoC bond in the coenzyme by increasing both k f and k r without significantly affecting K eq ( i.e. by a kinetic effect); the protein therefore labilises the C0C bond by changing K eq ( i.e. by a thermodynamic effect). The evidence indicates ( cf. the predictions in ref. ) that in there B 12-dependent enzymes the protein (1) uses steric distortion ( cf. also the non-enzymatic haemoglobins ) (2) to change a key equilibrium (as dinstinct from rate) consntant ( cf. also the peroxidases [3, 17]), and (3) acts as a molecular switch (with the red and yellow forms of the co-enzymes indicating the ‘off’ and ‘on’ positions respectively), triggered by the binding of the substrate, in order to generate the dangerously active radical (R·) only when the substrate is present.