Virus-encoded Shemin pathway highlights the importance of tetrapyrrole metabolism during host infection

ABSTRACT Tetrapyrroles such as heme, chlorophyll, or vitamin B 12 are among the most complex molecules synthesised by nature and play a crucial role in many vital processes such as respiration, photosynthesis, methanogenesis, and catalysis. All modified tetrapyrroles are derived from the common precursor molecule 5-aminolevulinic acid (5-ALA). However, 5-ALA can be synthesised in two different ways. While alphaproteobacteria, mammals, and birds use the so-called Shemin pathway, all other bacteria, archaea, and plants use the C5 pathway. Here, we present evidence for the presence of 5-ALA synthase genes of the Shemin pathway in the genomes of viruses (v alaS ) that infect bacteria (bacteriophages) in marine and freshwater environments. These genes either occur in a three-gene cassette with two heme catabolising enzymes involved in linear tetrapyrrole biosynthesis, as broken cassettes or as individual genes. v alaS encodes a functional enzyme, as shown by the enzymatic turnover of the co-substrates succinyl-Coenzyme A and glycine in an Escherichia coli strain overexpressing v alaS . Phylogenetic analysis in combination with three-dimensional structure prediction supported our data that the viral sequences encode active enzymes. Interestingly, the viral v alaS sequence is capable of functionally complementing a 5-ALA-auxotrophic Escherichia coli strain, which lacks one of the two enzymes of the C5 pathway. Host prediction suggests that different v alaS carrying phages might infect bacteria that either utilise the Shemin or the C5 pathway for 5-ALA biosynthesis. Our results thus support the hypothesis that metabolic reprogramming and maintenance of the host bacterium’s energy metabolism are crucial during bacteriophage infection and that tetrapyrroles play a key role in this process.