Molecular hijacking of siroheme for the synthesis of heme and d ₁ heme

Abstract

Modified tetrapyrroles such as chlorophyll, heme, siroheme, vitamin B 12 , coenzyme F 430 , and heme d 1 underpin a wide range of essential biological functions in all domains of life, and it is therefore surprising that the syntheses of many of these life pigments remain poorly understood. It is known that the construction of the central molecular framework of modified tetrapyrroles is mediated via a common, core pathway. Herein a further branch of the modified tetrapyrrole biosynthesis pathway is described in denitrifying and sulfate-reducing bacteria as well as the Archaea. This process entails the hijacking of siroheme, the prosthetic group of sulfite and nitrite reductase, and its processing into heme and d 1 heme. The initial step in these transformations involves the decarboxylation of siroheme to give didecarboxysiroheme. For d 1 heme synthesis this intermediate has to undergo the replacement of two propionate side chains with oxygen functionalities and the introduction of a double bond into a further peripheral side chain. For heme synthesis didecarboxysiroheme is converted into Fe-coproporphyrin by oxidative loss of two acetic acid side chains. Fe-coproporphyrin is then transformed into heme by the oxidative decarboxylation of two propionate side chains. The mechanisms of these reactions are discussed and the evolutionary significance of another role for siroheme is examined.

Illuminating the black box of B 12 biosynthesis

“…Second is the observation that a mixture containing all pathway enzymes functions more effectively than individual enzymes to produce product. This finding is not unlike what has been reported for siroheme biosynthesis (7,11) and hinted at for protoheme synthesis (12). Given the reactivity of tetrapyrrole biosynthetic pathway intermediates, it is not a surprise that evolution has designed pathway enzymes to hold on to products until downstream acceptors are available.…”

“…The product of this common pathway is uroporphyrinogen III. From here, synthesis of chlorophyll and protoheme proceed to the shared precursor protoporphyrin IX via an identical route, whereas synthesis of siroheme and heme d 1 use a unique and perhaps more ancient pathway in which the macrocycle is oxidized and methylated before iron insertion (7,8). Despite its biological importance in methanogenesis, factor F 430 's biosynthetic pathway has yet to be elucidated, although it shares the common pathway to uroporphyrinogen III.…”

Noncanonical coproporphyrin-dependent bacterial heme biosynthesis pathway that does not use protoporphyrin

“…Among genomes that possess AhbD, ∼60% contain HemQ and do not contain AhbA, AhbB, and AhbC. This phylogenetic occurrence profile strongly indicates that coproheme decarboxylase AhbD, discovered originally as part of the siroheme-to-protoheme pathway (14,16), can also function in the HemQ-based coproporphyrin-dependent heme biosynthesis route described in this work. Given that AhbD is an anaerobic, radical SAM enzyme and that HemQ functions in the presence of oxygen, the presence of both coproheme decarboxylases in a single organism mimics the presence of an anaerobic coproporphyrinogen decarboxylase (HemN) and aerobic (HemF) coproporphyrinogen decarboxylase in many Gramnegative bacteria.…”

“…For the oxygen-independent HemN, Jahn and coworkers (2, 7) have presented evidence that this radical SAM enzyme forms a substrate radical by hydrogen abstraction at the β-carbon of the propionate side chain as the first step in the reaction sequence. For the iron-sulfur cluster containing the radical SAM enzyme AhbD, it has been proposed that it uses the same reaction mechanism as HemN, which may be reasonable, given that both are radical SAM enzymes that function in the absence of oxygen (14,16).…”

“…This pathway, named the "alternative heme biosynthesis" path (or ahb), has now been characterized by Warren and coworkers (15) in sulfatereducing bacteria. In the ahb pathway, siroheme, synthesized from uroporphyrinogen III, can be further metabolized by successive demethylation and decarboxylation to yield protoheme (14,15) (Fig. 1 and Fig.…”