My favorite metabolic pathway is the production of siroheme

Siroheme

My favorite metabolic pathway is the production of siroheme in Geobacter sulfurreducens.

Sulphur (S) and nitrogen (N) are essential elements for all life. In plants and bacteria, sulfur is mainly taken up from the soil as sulphate and can be metabolized into the essential amino acids cystine and methionine. 

Animals cannot reduce reduce sulphate and cannot produce these two amino acids.  The essential sulfur containing amino acids cysteine and methionine must be taken in by diet (Tripathy, Sherameti, & Oelmüller, 2010)





Siroheme is a porphyrin.  Porphyrins are synthesized in the mitochondria and cytosol although there is some variation where the steps occur  between organisms.  Some steps may take place in  the mitochondria is one and cytosol in the other. 

They begin as simple amino acids and can form by one of two routes. Siroheme synthesis in G. sulfurreducens begins at the C5 pathway and starts out as glutamate. Porphyrin synthesis occurs along the Shemin pathway and is very conserved throughout all domains of life (Piao, Kiatpapan, Yamashita, & Murooka, 2004).

Siroheme pathway

(Tanaka & Tanaka, 2007)

Siroheme synthesis diverges from the Shemin pathway at step six at the heme precursor uroporphyrinogen III (Urogen III).  Siroheme synthesis plays a major role in converting sulfite to a biologically useful sulfide, which can be incorporated into the organic compound homocysteine (“Siroheme,” 2011).

The metabolic pathway for siroheme synthesis was downloaded from Kyoto Encyclopedia of Genes and Genomes from the porphyrin synthesis pathway (KEGG).



Siroheme pathway



The pathway for our discussion will begin at 5-aminolevulinate or δ-aminolevulinic acid (ALA).  There are at least five genes involved in the production, HemL, HemB, HemC, HemD, and CysG that produce the enzymes for siroheme synthesis.

Step 1       

1a. The first step in siroheme synthesis involves the condensation of glutamate (C-5 pathway) with succinylcoenzyme A (succinyl-CoA), which forms δ-aminolevulinic acid (ALA). In all organisms that produce heme, aminolevulinic acid synthase (ALAS) catalyzes the production of ALA.  ALAS uses vitamin B6, pyridoxal 5- phosphate, as a cofactor.

1b.  Following synthesis, ALA is exported from the mitochondria by an unknown

mechanism.  Two molecules of ALA are converted to porphobilinogen (PBG) in a condensation reaction catalyzed by aminolevulinic acid dehydratase (ALAD) (HemB).   ALAD from plants and many bacteria requires magnesium as a co-facter. 

PBG is the pyrrole precursor utilized by all living systems for the biosynthesis of tetrapyrroles, including hemes, chlorophylls, and corrins.

Step 2        

Four PBG molecules are combined to form a cyclic tetrapyrrole. This is done with the help of two enzymes.  Porphobilinogen deaminase (PBGD) and hydroxymethylbilane synthase (HMBS) (HemC) catalyzes the formation of the linear tetrapyrrole – hydroxymethylbilane (HMB) – from four molecules of PBG.

Step 3

HMB is unstable and is quickly converted by methylation to uroporphyrinogen III (UROgenIII) by uroporphyrinogen III synthase (UROS) (HemD). UROS catalyzes ring closure to form an asymmetrical macrocycle. 

**Here porphyrin synthesis diverges for different synthesis pathways, such as heme, siroheme, chlorophyll, and phytochromobilin.

**Methylation drives the reaction towards siroheme synthesis, **decarboxylation steers the reaction toward heme and chlorophyll synthesis (Tripathy et al., 2010).

Step 4

Uroporphyrinogen III is methylated twice with uroporphyrinogen III methyltransferase (Upm) (CysG) into precorrin 2 for siroheme synthesis.

**Decarboxylation by uroporphyrinogen III decarboxylase drives the reaction towards coproporphyrinogen III leading to chlorophyll and heme biosynthesis.

Step 5

Precorrin 2 is dehydrogenated by the enzyme precorrin-2 dehydrogenase (CysG) to form sirohydrochlorin.

Step 6

Iron (Fe+2) is inserted to the center of the tetrapyrrole with the enzyme sirohydrochlorin ferrochelatase (CysG) to form siroheme (Tripathy et al., 2010). 

Regulation:
I have not found any literature for the regulation of siroheme.  Siroheme is an iron-containing isobacteriochlorin essential for nitrite and sulfite reduction reactions (Severance & Hamza, 2009).

Bibliography

(Kanehisa_Laboratories). (2011). Porphyrin and chlorophyll metabolism - Geobacter sulfurreducens. KEGG: Kyoto Encyclopedia of Genes and Genomes. Retrieved September 5, 2012, from http://www.genome.jp/kegg-bin/show_pathway?gsu00860

Piao, Y., Kiatpapan, P., Yamashita, M., & Murooka, Y. (2004). Effects of expression of hemA and hemB genes on production of porphyrin in Propionibacterium freudenreichii. Applied and environmental microbiology, 70(12), 7561-6. doi:10.1128/AEM.70.12.7561-7566.2004

Severance, S., & Hamza, I. (2009). Trafficking of heme and porphyrins in metazoa. Chemical reviews, 109(10), 4596-4616. doi:10.1021/cr9001116.Trafficking

Siroheme. (2011).Wikipedia. Retrieved November 5, 2012, from http://en.wikipedia.org/wiki/Siroheme

Tanaka, R., & Tanaka, A. (2007). Tetrapyrrole biosynthesis in higher plants. Annual review of plant biology, 58, 321-46. doi:10.1146/annurev.arplant.57.032905.105448

Tripathy, B. C., Sherameti, I., & Oelmüller, R. (2010). Siroheme: an essential component for life on earth. Plant signaling & behavior, 5(1), 14-20. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2835951&tool=pmcentrez&rendertype=abstract

(Kanehisa_Laboratories). (2011). Porphyrin and chlorophyll metabolism - Geobacter sulfurreducens. KEGG: Kyoto Encyclopedia of Genes and Genomes. Retrieved September 5, 2012, from http://www.genome.jp/kegg-bin/show_pathway?gsu00860

Piao, Y., Kiatpapan, P., Yamashita, M., & Murooka, Y. (2004). Effects of expression of hemA and hemB genes on production of porphyrin in Propionibacterium freudenreichii. Applied and environmental microbiology, 70(12), 7561-6. doi:10.1128/AEM.70.12.7561-7566.2004

Severance, S., & Hamza, I. (2009). Trafficking of heme and porphyrins in metazoa. Chemical reviews, 109(10), 4596-4616. doi:10.1021/cr9001116.Trafficking

Siroheme. (2011).Wikipedia. Retrieved November 5, 2012, from http://en.wikipedia.org/wiki/Siroheme

Tripathy, B. C., Sherameti, I., & Oelmüller, R. (2010). Siroheme: an essential component for life on earth. Plant signaling & behavior, 5(1), 14-20. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2835951&tool=pmcentrez&rendertype=abstract