Figure 1.
Heme biosynthesis pathway in animals.
The substrate and product are indicated for each enzyme and the subcellular localization of each enzyme is also shown (cytosol or mitochondria). Each enzyme is coded from one to eight according to the linear order of the pathway. Also shown are the processes by which hydroxymethylbilane, the substrate of UROS, can be non-enzymatically cyclized to form uroporphyrinogen I, leading to uroporphyrin I or coproporphyrin I, and the process by which uroporphyrinogen III, the product of UROS, can be auto-oxidized to form uroporphyrin III. Protoporphyrinogen, the substrate of PPO, can be auto-oxidized to form protoporphyrin.
Figure 2.
Selection pressure on heme biosynthesis genes in animals.
ω values (dN/dS) were estimated with the M0 model for the eight heme biosynthesis genes in animals (A). The distribution of ω values (B), the nonsynonymous substitution rate, dN (C), and the synonymous substitution rate, dS (D). The order of genes follows the linear order of their pathway positions (Figure 1).
Table 1.
Comparison of ω values among eight genes to test the significance of the ω variations among genes.
Table 2.
Selection pressure of genes of heme-biosynthesis pathway by employing the branch model.
Table 3.
Positive selection in the different lineages of genes of heme biosynthesis pathway.
Figure 3.
Three-dimensional view of the evolutionarily conserved DNase-hypersensitive sites in intron sequences.
For each gene in the biosynthesis pathway (ALAS1 and ALAS2 are treated separately because they are different genes located on different chromosomes), the length of the intersection of the DNA sequence that is evolutionarily conserved across vertebrates and DNase-hypersensitive sites is indicated on the z-axis. The intron ID is provided on the x-axis. Genes from ALAS1 to FECH are shown on the y-axis and are coded from one to eight according to the linear order of the pathway. (Figure 1).
Table 4.
IRE in 5′UTR.
Table 5.
IRE in intron.
Figure 4.
Potential iron-responsive elements (IREs) in the introns and intron-exon boundaries of UROS genes.
IREs depicted as stem-loop structures are shown in the corresponding intron regions. UROS exon and intron IDs from four species are indicated. The conserved splicing acceptor site AG and the unpaired nucleotide of the IRE structure are also shown.
Figure 5.
Sequence alignment of the IREs at the intron-exon boundaries of UROS from four species.
“>” and “<” represent the base pairing of the RNA secondary structure. The potential IRE consensus loop sequence, CAGUGN, and the unpaired nucleotide G are also shown with respect to the location of the IRE hairpin. The intron-exon boundary is indicated as |.
Table 6.
HRM_t in protein sequence.
Table 7.
HRM_r in protein sequence.
Figure 6.
Heme-regulatory motifs (HRMs) in PBGS and PBGD.
Multiple sequence alignments of PBGS (A) and PBGD (B) are shown, with HRM_t and HRM_r colored orange and green, respectively. Amino acid numbers for HRM_t and HRM_r are also shown according to the first protein sequence in the alignment.
Table 8.
Multiple regulatory potentials in heme biosynthesis pathway.