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, 8 (3), 594-607

Structure and Function of Lactate Dehydrogenase From Hagfish

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Structure and Function of Lactate Dehydrogenase From Hagfish

Yoshikazu Nishiguchi et al. Mar Drugs.

Abstract

The lactate dehydrogenases (LDHs) in hagfish have been estimated to be the prototype of those in higher vertebrates. The effects of high hydrostatic pressure from 0.1 to 100 MPa on LDH activities from three hagfishes were examined. The LDH activities of Eptatretus burgeri, living at 45-60 m, were completely lost at 5 MPa. In contrast, LDH-A and -B in Eptatretus okinoseanus maintained 70% of their activities even at 100 MPa. These results show that the deeper the habitat, the higher the tolerance to pressure. To elucidate the molecular mechanisms for adaptation to high pressure, we compared the amino acid sequences and three-dimensional structures of LDHs in these hagfish. There were differences in six amino acids (6, 10, 20, 156, 269, and 341). These amino acidresidues are likely to contribute to the stability of the E. okinoseanus LDH under high-pressure conditions. The amino acids responsible for the pressure tolerance of hagfish are the same in both human and hagfish LDHs, and one substitution that occurred as an adaptation during evolution is coincident with that observed in a human disease. Mutation of these amino acids can cause anomalies that may be implicated in the development of human diseases.

Keywords: evolutionary medicine; hagfish; high-pressure adaptation; lactate dehydrogenase.

Figures

Figure 1
Figure 1
Patterns of the Cyclostomata LDH isozymes. LDH-A4 bands are detected in skeletal muscle from all cyclostomata examined and in the E. japonica heart, whereas B4 bands are expressed only in hearts from hagfish. Note that labels (A4, A3B1, A2B2, A1B3, and B4) indicate five human tetrameric isozymes and do not correspond to Cyclostomata LDH isozymes. Reproduced with permission from the Zoological Society of Japan [10].
Figure 2
Figure 2
Thermal stability of LDH from hagfish. ▪: E. okinoseanus LDH-A4, ●: E. burgeri LDH-A4.
Figure 3
Figure 3
Effects of hydrostatic pressure on LDHs from hagfish E. okinoseanus, E. burgeri and P. atami.
Figure 4
Figure 4
Differences in amino acid sequences of LDH-A4 from E. okinoseanus, P. atami, and E. burgeri. There were differences in six amino acid residues (6, 10, 20, 156, 269, and 341) when comparing the LDHs of the three hagfishes. a: Deep-sea type (E. okinoseans), b: shallow-sea type (E. burgeri). Reproduced with permission from the Springer Japan [11].
Figure 5
Figure 5
Prediction of the three-dimensional structure of hagfish LDH-A4. A: Functional sites of amino acid residues common to the three hagfish LDHs (a, b, c). B: Amino acid residues that vary with LDHs of the three hagfishes (6, 10, 20, 156, 269, and 341) and the region specific to LDHs of hagfish (220–227).
Figure 6
Figure 6
Analysis of amino acid sequences of LDH. C1–C10: Common regions, S1, S2: Cyclostomata-specific regions, IGS1-IGS3: isozyme (LDH-B) group-specific regions. Reproduced with permission from the Zoological Society of Japan [10].
Figure 7
Figure 7
Phylogenetic tree of Cyclostomata LDHs. The tree topology and branch lengths were obtained using the neighbor-joining algorithm. The outgroup for this analysis was lamprey LDH. In this case, 1000 bootstrap pseudoreplications were analyzed, and the number near the node indicates the percentage of optimal trees in which this node appeared; values <50% are not shown. The scale at the bottom of this figure indicates branch length in substitutions per site. Reproduced with permission from the Zoological Society of Japan [10].
Figure 8
Figure 8
Three-dimensional structures of LDH. Reproduced with permission from the Zoological Society of Japan [10].
Figure 9
Figure 9
Three-dimensional structures of hagfish LDH-A and human LDH-A. Reproduced with permission from the Ogata Institute for Medical and Chemical Research [25].

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