Molecular hijacking of siroheme for the synthesis of heme and d1 heme

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2011; 108(45):18260-5. DOI: 10.1073/pnas.1108228108
Source: PubMed


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.

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    • "S. aureus haem biosynthesis: from uroporphyrinogen III to haem 473 undergoes a bis-decarboxylation to give didecarboxysirohaem (DDSH) in a reaction mediated by sirohaem decarboxylase (AhbA-B) (Palmer et al., 2014). DDSH is subsequently converted into Fe-coproporphyrin III in a radical SAM-mediated process via AhbC, which oversees the removal of the two acetic acid side-chains attached to rings A and B of the substrate (Bali et al., 2011). The last step involves another radical SAM enzyme (AhbD) that is analogous to the HemN reaction in that it catalyses the oxidative decarboxylation of the two propionic acid sidechains attached to C3 and C8 (Fig. 1) via a dehydrogenation process that yields vinyl side-chains, i.e. it converts Fe-coproporphyrin III to protohaem IX (Lobo et al., 2014). "
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    ABSTRACT: Haem is a life supporting molecule that is ubiquitous in all major kingdoms. In Staphylococcus aureus, the importance of haem is highlighted by the presence of systems both for the exogenous acquisition and endogenous synthesis of this prosthetic group. In this work, we show that in S. aureus the formation of haem involves the conversion of coproporphyrinogen III into coproporphyrin III by coproporphyrin synthase HemY, insertion of iron into coproporphyrin III via ferrochelatase HemH, and oxidative decarboxylation of Fe-coproporphyrin III into protohaem IX by Fe-coproporphyrin oxidase/dehydrogenase HemQ. Together, this route represents a transitional pathway between the classic pathway and the more recently acknowledged alternative biosynthesis machinery. The role of the haem biosynthetic pathway in the survival of the bacterium was investigated by testing for inhibitors of HemY. Analogues of acifluorfen are shown to inhibit the flavin-containing HemY, highlighting that this as a suitable target for the development of drugs against S. aureus. Moreover, the presence of this transitional pathway for haem biosynthesis within many Gram-positive pathogenic bacteria suggests that this route has the potential not only for the design of antimicrobials but also for the selective discrimination between bacteria operating different routes to the biosynthesis of haem. This article is protected by copyright. All rights reserved.
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    • "Kuenenia stuttgartiensis' and 'Ca. Scalindua profunda' cells highly expressed heme proteins, including Hzs, Hdh and hydroxylamine dehydrogenase (Hao) (Kartal et al., 2011; van de Vossenberg et al., 2013), suggesting that large amounts of iron are necessary for coordination at the centre of the heme molecules (Klotz et al., 2008; Bali et al., 2011). Iron is also required for some redox-active molecules other than the heme, including the iron–sulfur cluster (Ayala-Castro et al., 2008). "
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    • "In contrast, a new branch of tetrapyrrole biosynthesis has been recently described that is responsible for an alternative haem biogenesis pathway that also accounts for the synthesis of haem d1 (Bali et al., 2011; 2014a,b). This route employs sirohaem, the prosthetic group of sulphite and nitrite reductases, as an intermediate (Fig. 1). "
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