Redox, haem and CO in enzymatic catalysis and regulation

Abstract

The present paper describes general principles of redox catalysis and redox regulation in two diverse systems. The first is microbial metabolism of CO by the Wood-Ljungdahl pathway, which involves the conversion of CO or H2/CO2 into acetyl-CoA, which then serves as a source of ATP and cell carbon. The focus is on two enzymes that make and utilize CO, CODH (carbon monoxide dehydrogenase) and ACS (acetyl-CoA synthase). In this pathway, CODH converts CO2 into CO and ACS generates acetyl-CoA in a reaction involving Ni·CO, methyl-Ni and acetyl-Ni as catalytic intermediates. A 70 Å (1 Å=0.1 nm) channel guides CO, generated at the active site of CODH, to a CO 'cage' near the ACS active site to sequester this reactive species and assure its rapid availability to participate in a kinetically coupled reaction with an unstable Ni(I) state that was recently trapped by photolytic, rapid kinetic and spectroscopic studies. The present paper also describes studies of two haem-regulated systems that involve a principle of metabolic regulation interlinking redox, haem and CO. Recent studies with HO2 (haem oxygenase-2), a K+ ion channel (the BK channel) and a nuclear receptor (Rev-Erb) demonstrate that this mode of regulation involves a thiol-disulfide redox switch that regulates haem binding and that gas signalling molecules (CO and NO) modulate the effect of haem.

Figure 1. The Wood–Ljungdahl pathway of anaerobic CO₂ and CO fixation

The pathway involves the six-electron reduction of CO₂ to methyl-tetrahydrofolate (CH₃-H₄folate), followed by the methyltransferase (MeTr)-catalysed transfer of the methyl group to CFeSP. CODH reduces CO₂ to CO, which is condensed with the methyl group and CoA to generate acetyl-CoA.

Figure 2. Random mechanism of the ACS reaction

Shown are the random-order binding of CO and the methyl group to ACS, followed by C–C bond formation and thiolysis by CoA to generate acetyl-CoA.

Figure 3. The mechanism of acetyl-CoA formation by ACS

Figure 4. Domains of HO1 and HO2

HRMs are CP (Cys-Pro) motifs that in HO2 regulate binding of haem. TM helix is the C-terminal transmembrane helix that is found in both HO1 and HO2. See the text for details.

Figure 5. Overlay of HO1 and HO2

The structures of these proteins are known for the core catalytic domains. The region beyond Glu²⁴⁵ in HO2 appears to be unstructured, and the electron density for this region of the protein was not present in the diffraction data.