Table 2.
Structural and functional alterations in disease-causing hE3 variants studied
| Substitution | Affected region | Former functional studies | Present crystallograpic study | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Residual enzymatic activity (% of control) | Source | Genotype in patient | Reference | Major structural alterations | |||||
| E3 | PDHc | KGDHc | BCKDHc | ||||||
| P453L | Active site | 6 | – | – | – | F | P453L/K37E | (44) | Extensively perturbed active site including catalytic residues. |
| 4–9 | – | – | – | RP | – | (12) | |||
| ND | – | – | – | RP in yeast cell | – | (72) | |||
| G194C | NAD+/NADH-binding domain | 7–21M, 8–34F |
11–12M, 20F |
12–19M | – | M, F | G194C/G194C | (30–32,34) | Altered charge equilibrium and induced dynamics near the nicotinamide-binding site. |
| 8–20 | – | – | – | M | Y35X*/G194C | (30) | |||
| 10–30 | 69 | 44 | 58 | F | G194C/I12T | (26) | |||
| 47–100† | 29 | 61 | – | RP | – | (10,12,36,50) | |||
| G426E | Interface domain | – | 44 | 22 | 43 | F | I40fs*/G426E | (51) | |
| R460G | 1.5L, 14F | 26L, 11F | 20F | – | L, F | Y35X*/R460G | (52) | Perturbed H+/H2O channel forming residues (to various degrees) | |
| 10–91† | – | – | – | RP | – | (12,36–38,73) | |||
| R447G | 20 | 63 | 0 | 56 | F | R447G/R447G | (54) | ||
| 54–92† | – | – | – | RP | – | (36,37) | |||
| I445M | ND | 97‡ | – | – | F | I445M/I445M | (56) | ||
*Numbering reflects the immature protein sequence containing the 35 amino acid mitochondrial leader sequence.
†Enzymatic activities were measured under different assay conditions.
‡% of lower limit of control range.
Abbreviations:
ND = not detectable
F = fibroblasts
RP = recombinant protein
M = muscle homogenate
L = lymphocytes
fs = frame shift