Table 2.
Copper-dependent Enzymes and basic properties.
| Enzyme | OMIM | EC-no. | Cofactor | Cu Donor | Cu Loading Site | Cu Chaperone | Subcellular Localization | ATP7A-Linked Cu Deficiency Symptoms | |
|---|---|---|---|---|---|---|---|---|---|
|
ATOX1 regulated
Copper Pumps |
ATP7A | 300011 | 7.2.2.8 | Mg; ATP Cu-ATOX1 allosteric |
ATOX1 Cu-GSH |
Cytosol | ATOX1 piggy-backing | SP, TGN, PM | Cu storage in tissues, low in brain, liver, plasma; S-Cu diagnostic after 1.5 mo |
| ATP7B | 606882 | 7.2.2.8 | Mg; ATP Cu-ATOX1 allosteric |
ATOX1 Cu-GSH |
Cytosol | ATOX1 piggy-backing | SP, TGN, secretory vesicles | Low activity in brain and liver; Fe accumulation; icterus, steatosis | |
| Copper Reductases | STEAP1 | 604415 | 1.16.1.- | Heme; NAD | Cu-His | EC redox | NAp | PM, endosomes |
Cu and Fe accumulation on plasma membranes and vesicles; hypochromic anemia |
| STEAP2 | 605094 | 1.16.1.- | Heme; NAD | Cu-His | EC redox | NAp | PM, Golgi | ||
| STEAP3 | 609671 | 1.16.1.- | Heme; NADP | Cu-His | EC redox | NAp | PM, endosomes |
||
| STEAP4 | 611098 | 1.16.1.- | Heme; NADPH | Cu-His | EC redox | NAp | PM, ER, Golgi endosomes nucleus, MIT |
||
| CYBDR | 605745 | 1.-.-.- | Heme; ascorbate | Cu-His | EC redox | NAp | PM | ||
| Copper Oxidases | CP | 117700 | 1.16.3.1 | Cu; ascorbate | ATP7B | ERGIC | NK | EC | CP low in plasma; diagnostic after 1½ month; Cu and Fe storage |
| FV+VIII | 612309 300841 | 1.16.3.1 | Cu; ascorbate | ATP7B | ERGIC | NK | EC | Mild clotting deficiency | |
| HEPH | 300167 | 1.16.3.1 | Cu; ascorbate | ATP7A | ERGIC | NK | Vesicles | Cu and Fe intracellular storage; AMD | |
| HEPH1L | 618455 | 1.16.3.1 | Cu; ascorbate | ATP7A | ERGIC | NK | cis-Golgi | Cutis laxa | |
| COX CuA (II) CuB (I) |
516040 516030 |
1.9.3.1 | Cu Cu;Heme |
Redox SCO1; SCO2; COA6 COX11 |
IMS IMS |
COX17 COX17 |
IMM | Low COX in brain and liver due to low Cu availability; High lactate in blood; Leigh-like symptoms; COX defects; ragged red fibers; hypotonia |
|
| Copper Quinone Amine Oxidases | LOX | 153455 | 1.4.3.1 | Cu; LTQ | ATP7A | cis-Golgi | HEPH1L redox | EC | Numerous connective tissue abnormalities: tortuous vessels, aortic aneurisms, and dissections, umbilical or inguinal hernias, bladder and bowel diverticulae, loose joint and skin, osteoporosis, lymphedema, lung infections; collectin defects with protein trafficking problems, and deficient activation of complement pathway; NAI-like; cataract |
| LOXL1 | 153456 | 1.4.3.1 | Cu; LTQ | ATP7A | cis-Golgi | Redox loading # | EC | ||
| LOXL2 | 606663 | 1.4.3.1 | Cu; LTQ | ATP7A | cis-Golgi | Redox loading # | ER, nucleus * | ||
| LOXL3 | 607163 | 1.4.3.1 | Cu; LTQ | ATP7A | cis-Golgi | Redox loading # | ER, nucleus * | ||
| LOXL4 | 607318 | 1.4.3.1 | Cu; LTQ | ATP7A | cis-Golgi | Redox loading # | EC | ||
| AOC1 | 104610 | 1.4.3.22 | Cu; TPQ | ATP7A | cis-Golgi | Redox loading # | EC | Ichthyosis, alopecia, inflammation, conjunctivitis, atopy, photophobia, keratitis, diarrhoea, gastrointestinal polyps | |
| AOC2 | 602268 | 1.4.3.21 | Cu; TPQ | ATP7A | cis-Golgi | Redox loading # | PM | ||
| AOC3 | 603735 | 1.4.3.21 | Cu; TPQ | ATP7A | cis-Golgi | Redox loading # | PM | ||
|
FGly
Generation |
SUMF1 | 607939 | 1.8.3.7 | Cu; Ca | ATP7A | ER | SUMF2 | SP | GAG accumulation in tissues and urine; metachromasia, Alder Reilly anomaly; overlapping clinical features of multiple sulfatase deficiency (MSD) mimicking metachromatic leukodystrophy, mucopolysaccharidosis (MPS), mucolipidosis (MLP), chondrodysplasia punctata, hydrocephalus |
|
FGly
Activated Sulfatases |
ARSA | 607574 | 3.1.6.8 | FGly; Ca | NAp | NAp | NAp | Lysosomes | |
| ARSB | 611542 | 3.1.6.12 | FGly; Ca | NAp | NAp | NAp | Lysosomes | ||
| ARSD | 300002 | 3.1.6.- | FGly; Ca | NAp | NAp | NAp | Lysosomes | ||
| ARSF | 300003 | 3.1.6.- | FGly; Ca | NAp | NAp | NAp | EC | ||
| ARSE | 300180 | 3.1.6.- | FGly; Ca | NAp | NAp | NAp | Golgi | ||
| ARSG | 610008 | 3.1.6.1 | FGly; Ca | NAp | NAp | NAp | Lysosomes | ||
| ARSH | 300586 | 3.1.6.- | FGly; Ca | NAp | NAp | NAp | PM | ||
| ARSI | 610009 | 3.1.6.- | FGly; Ca | NAp | NAp | NAp | EC | ||
| ARSJ | 610010 | 3.1.6.- | FGly; Ca | NAp | NAp | NAp | EC | ||
| ARSK | 610011 | 3.1.6.- | FGly; Ca | NAp | NAp | NAp | EC | ||
| GALNS | 612222 | 3.1.6.4 | FGly; Ca | NAp | NAp | NAp | Lysosomes | ||
| GNS | 607664 | 3.1.6.14 | FGly; Ca | NAp | NAp | NAp | Lysosomes | ||
| IDS | 300823 | 3.1.6.13 | FGly; Ca | NAp | NAp | NAp | Lysosomes | ||
| STS | 300747 | 3.1.6.2 | FGly; Ca | NAp | NAp | NAp | ER | ichthyosis, seborrhoea, hair changes | |
| Copper Amine Oxidases | DBH | 609312 | 1.14.17.1 | Cu; ascorbate | ATP7A | ER | MOXD1# | Vesicles; EC | High DA/NE; vomiting, hypotension, hypothermia, hypoglycemia |
| PAM PHM PAL |
170270 | 1.14.17.3 4.3.2.5 |
Cu; ascorbate Zn; Ca |
ATP7A NAp |
TGN NAp |
NK NAp |
Golgi Vesicles | Pain, seizure, anxiety, impaired wakening, temperature, weight and fluid balance | |
| TYR | 606933 | 1.14.18.1 | Cu; ascorbate | ATP7A | ER | TYRP1 TYRP2 |
Melanosomes | Albinism, visual and hearing problems | |
| MOXD1 | 609000 | 1.14.17.- | Cu; ascorbate | ATP7A | ER | - | ER | ~DBH deficiency | |
| Cu/Zn Superoxide Dismutases | SOD1 | 147450 | 1.15.1.1 | Cu; Zn Cu-CCS allosteric |
GSH ATP7A matrix NK |
Cytosol ER IMS NK |
CCS redox and piggy-backing CCS redox CCS |
Cytosol peroxisomes IMS nucleus |
Low SOD1 activity in nerve tissue and liver due to poor Cu availability; peroxisomal pathologies; motor neuron disease |
| SOD3 | 185490 | 1.15.1.1 | Cu; Zn | ATP7A | SP | NK | EC | Lung disease, angiopathy | |
| CCS | 603864 | NA | Cu;Zn | GSH ATP7A matrix nucleus |
Cytosol ER IMS nucleus |
NAp | Cytosol peroxisomes IMS nucleus |
Purkinje cell pathologies; ALS-like phenotype | |
| APP | 104760 | NA | Cu; Zn | NK | SP | NK | EC | Senecense, cerebral angiopathy | |
| APLP1 | 104775 | NA | Cu; Zn | NK | SP | NK | EC | ||
| APLP2 | 104776 | NA | Cu; Zn | NK | SP | NK | EC | ||
|
Cu-CCS
Regulated Enzyme |
BACE1 | 604252 | 3.4.23.46 | Cu-CCS allosteric |
CCS | SP | CCS | TGN | Poor neuronal growth |
#: indicated; *: histone biology; EC: extracellular; ER: endoplasmic reticulum; ERGIC: ER–Golgi intermediate compartment; GAG: glycoamino glycans; GHS: glutathione; IMM: inner mitochondrial membrane; IMS: intra mitochondrial space; MIT: mitochondria; NA: not assigned; NAI: non-accidental injuries; NAp: not applicable; NK: not known; PM: plasma membrane; SP: secretory pathway; TGN: trans-Golgi network.