Reduction of Biliverdins to Bilirubins: Its Metabolic Regulation Under Various Physiological Conditions

Abstract

Abstract: Heme and hemoproteins are degraded in mammals by oxidation to biliverdins. These linear tetrapyrroles are reduced to bilirubins by a cytosolic biliverdin reductase (BvR) at the rate of 250-400 mg per day. While the bulk of biliary biliverdin is biliverdin IX α , other isomers such as biliverdins IXβ and IXγ are formed under conditions of oxidative stress by the chemical degradation of hemoproteins, or from the degradation of abnormal hemoglobins. Rat liver BvR was found to. be a NADPH-dependent reductase with a broad substrate specificity, which efficiently reduces a large number of biliverdins as long as they carry two propionate side-chains. The enzyme was found to exist in three molecular forms, two of which (molecular forms 1 and 3) interconvert under conditions of oxidative stress or in the presence of oxidant species. The different molecular forms have different reduction rates for the biliverdin isomers, thus securing the efficient reduction of biliverdins to bilirubins under different physiological conditions. The molecular mechanism of the enzymatic reduction entails the protonation of the basic pyrrolenine nitrogen (N23) which results in a mesomeric positive charge on the neighboring meso C-10 carbon. The C-10 then undergoes a nucleophilic addition of the hydride released by the NADPH cofactor of BvR. Our studies have established the structural requirements for a biliverdin to be efficiently reduced to a bilirubin. This metabolic step gains relevance as synthetic hemes and metalloporphyrins are increasingly used in therapeutics.