Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways
Abstract
:1. Introduction
1.1. Physical And Chemical Aspects of the Oat-Mediated Reaction
1.1.1. Reaction
1.1.2. A Key Feature: Spontaneous Cyclization of GSA
1.1.3. Kinetic Characteristics of OAT
1.2. Inhibitors
2. Structure of OAT
2.1. Primary Sequence and Leading Peptide
2.2. The Three-Dimensional Structure
2.3. The Active Site
3. Synthesis and Fate of OAT—From Gene to Protein
3.1. From Gene to Protein
3.1.1. Genes Encoding OAT
3.1.2. Transcription
3.1.3. Translation
3.2. Changes in Protein
3.2.1. Peptide Maturation
3.2.2. Post-Translational Modifications
3.3. Life and Death of the Protein
3.3.1. Interaction with Other Proteins
3.3.2. OAT Degradation
4. Localization of OAT
4.1. Cellular Localization
4.2. Tissue Localization
4.3. OAT in the Liver
4.4. OAT in the Digestive Tract
4.5. OAT in the Kidney
4.6. OAT in the Brain and the Nervous and Sensory System
4.7. OAT in the Other Tissues
5. The Role of OAT in Ornithine Fluxes
5.1. Fluxes in Non-Mammals: Orn Degradation
5.1.1. Prokaryotes
5.1.2. Plants
5.1.3. Fungi
5.1.4. Unicellular Eukaryotes
5.2. Fluxes in Mammals: A Subtle Compromise between Orn Degradation and Orn Synthesis
5.2.1. OAT and Orn Degradation
5.2.2. OAT and Orn Synthesis
6. OAT in Health and Disease
6.1. OAT and the Development of Mammals
6.1.1. OAT and Arg Supply in the Pre-Weaning Period
6.1.2. Changes in Tissue-Specific OAT Expression
6.1.2.1. Pre-Weaning Period
6.1.2.2. Weaning Period
6.1.2.3. Post-Weaning Period and Puberty
6.1.3. Other Implications
6.2. Consequences of OAT Deficiency: Gyrate Atrophy of the Choroid and Retina (GA)
6.2.1. Overview
6.2.2. Pathophysiology
6.2.3. Diagnosis
6.2.4. Diagnosis in Newborns
6.2.5. Therapeutic Approaches
6.3. OAT Inhibition As A Possible Therapeutic Strategy
6.3.1. Potential Utility of OAT Inhibitors for the Treatment of Cancer
6.3.2. Treatment of Hyperammonemia
6.3.3. OAT in Sepsis
7. Conclusions
Acknowledgments
Conflicts of interest
References
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Organ | Tissue | Species | Optimal pH | Michaelis constant (Km) | Activity | Reference | ||
---|---|---|---|---|---|---|---|---|
Orn | aKG | Value | Unit | |||||
Eye | Retina | Human | 7.6–8.0 | 3.7 | 1.72 | 218 ± 22 | nmol P5C/mg protein/h | [15] |
Bovine | 5.6 | 1.3 | [16] | |||||
Calf | 234 ± 26 | nmol P5C/mg protein/h | [15] | |||||
Rat | 324 ± 43 | nmol P5C/mg protein/h | [15] | |||||
Rabbit | 240 ± 24 | nmol P5C/mg protein/h | [15] | |||||
Iris (ciliary body) | Rat | 308 ± 26 | nmol P5C/mg protein/h | [15] | ||||
Rabbit | 227 ± 28 | nmol P5C/mg protein/h | [15] | |||||
Calf | 218 ± 26 | nmol P5C/mg protein/h | [15] | |||||
Human | 165 ± 17 | nmol P5C/mg protein/h | [15] | |||||
Liver | Rat | 2.8 | [6] | |||||
458 ± 56 | nmol P5C/mg protein/h | [15] | ||||||
7.8 | 2.7 | 3.0 | 11 | µmol/mg protein/min | [17] | |||
*** | 8.0 | 0.56 | 0.91 | [18] | ||||
8.15 | [19] | |||||||
1 | 0.7 | [14] | ||||||
Mouse | 7.5 | 4,8 | 0.7 | 10,8 | µmol/mg protein/min | [17] | ||
** | 1.2 ± 0.11 | 2 ± 0.5 | 0,75 | µmol P5C/mg proteine/h | [20] | |||
Rabbit | 317 ± 34 | nmol P5C/mg protein/h | [15] | |||||
Trout ** | 7.3 | 7.5 ± 0.8 | 0.88 ± 0.2 | 0,033 | µmol/min | [21] | ||
Isolated mitochondria | Rat * | 4 | 0,15 | 25 | nmol/min/mg protein | [22] | ||
Kidney | Rat | |||||||
*** | 8.0 | 0.59 | 0.91 | 920 | units/mg protein | [18] | ||
Rabbit | 674 ± 48 | nmol P5C/mg protein/h | [15] | |||||
Brain | Rat | 488 ± 42 | nmol P5C/mg protein/h | [15] | ||||
Rat | 8 | 1,67 | 0,5 | [23] | ||||
Rabbit | 112 ± 18 | nmol P5C/mg protein/h | [15] | |||||
69 ± 18 | nmol P5C/mg protein/h | [15] | ||||||
Mouse ** | 1.1 ± 0.1 | 2.6 | 1.1 | µmol P5C/mg protein/h | [20] | |||
Cortical interneurons | Mouse * | 0.8 ± 0.3 | [24] | |||||
Cerebellar granule cells | Mouse * | 4.7 ± 0.9 | [24] | |||||
Astrocytes | Mouse * | 4.3 ± 2.2 | [24] | |||||
Small intestine | Rat *** | 8.0 | 0.60 | 0.95 | [18] | |||
Modiolus demissus | [25] | |||||||
Plasmodium falciparum | 3.95 ± 1.04 | 0.65 ± 0.21 | [26] | |||||
Pea (Pisum sativorum) | 8.8 | 15 | 2 | 60.4 | nmol/mg/s | [27] | ||
Mothbean (Vignia aconitifolia) | 8 | 2 | 0.75 | [28] |
Inhibitor | Structure | Nature | Experimental Conditions | Ki or % Inhibition | OAT Origin | Reference |
---|---|---|---|---|---|---|
α-Amino acids | ||||||
l-Canaline | Irreversible | 8 U OAT, 37 °C, pH 8, 0.05 mM PO43− buffer 0.1 mM PLP, 175 mM Orn, 35 mM aKG | Ki: 2 µM | Rat (liver) | [39] | |
Irreversible, noncompetitive | pH 8, 0.05 mM PO43− buffer 0.01 mM PLP, 20 mM Orn, 10 mM aKG | Rat (liver) | [40] | |||
l-Canavanine | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 100% at 25 mM | Rat (liver) | [6] | ||
0.5 U OAT; 50 mM Orn | 23% at 20 mM | Rat (kidney) | [41] | |||
l-Norvaline | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 59% at 50 mM | Rat (liver) | [6] | ||
pH 8, 50 mM PO43− buffer 0.1 mM PLP, 10 mM Orn, 5 mM aKG | 50% at 10 mM | Rat (liver) | [14] | |||
0.5 U OAT; 50 mM Orn | 44% at 100 mM | Rat (kidney) | [41] | |||
l-Valine | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 47% at 25 mM | Rat (liver) | [6] | ||
0.5 U OAT; 50 mM Orn | 33% at 25 mM | Rat (kidney) | [41] | |||
Competitive for Orn; uncompetitive for aKG | pH 8, 50 mM PO43− buffer 0.1 mM PLP, 10 mM Orn, 5 mM aKG | 2.0 mM (forward reaction) | Rat (liver) | [14] | ||
Noncompetitive for Glu and P5C | 37 °C, pH 8, 50 mM Tris-HCl buffer 0.1 mM PLP, 5 mM P5C, 40 mM l-Glu | 20 mM (reverse reaction) | Rat (liver) | [14] | ||
Competitive | pH 8, 12.5 mM Tris-HCl buffer 0.025 mM PLP, 5 mM Orn, 2.5 aKG | 28% at 2.5 mM 41% at 5 mM | Rat (brain) | [23] | ||
l-Isoleucine | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 27% at 25 mM | Rat (liver) | [6] | ||
pH 8, 50 mM PO43− buffer 0.1 mM PLP, 10 mM Orn, 5 mM aKG | 30% at 10 mM | Rat (liver) | [14] | |||
0.5 U OAT; 50 mM Orn | 19% at 25 mM | Rat (kidney) | [41] | |||
pH 8, 12.5 mM Tris-HCl buffer 0.025 mM PLP, 5 mM Orn, 2.5 aKG | 29% at 2.5 mM 29% at 5 mM | Rat (brain) | [23] | |||
l-Leucine | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 21% at 25 mM | Rat (liver) | [6] | ||
pH 8, 50 mM PO43− buffer 0.1 mM PLP, 10 mM Orn, 5 mM aKG | 20% at 10 mM | Rat (liver) | [14] | |||
0.5 U OAT; 50 mM Orn | 17% at 25 mM | Rat (kidney) | [41] | |||
pH 8, 12.5 mM Tris-HCl buffer 0.025 mM PLP, 5 mM Orn, 2.5 aKG | 8% at 2.5 mM 22% at 5 mM | Rat (brain) | [23] | |||
Cysteine | pH 8, 12.5 mM Tris-HCl buffer 0.025 mM PLP, 5 mM Orn, 2.5 aKG | 48% at 2.5 mM 66% at 5 mM | Rat (brain) | [23] | ||
2,4-Diaminobutyrate | Competitive | 37 °C, pH 8, 50 mM PO43− buffer 175 mM Orn, 35 mM aKG | 25% at 10 mM 40% at 25 mM | Rat (liver) | [42] | |
γ-Amino acids | ||||||
γ-Aminobutyrate | Competitive | 37 °C, pH 8, 50 mM PO43− buffer 175 mM Orn, 35 mM aKG | 3.4 mM 70% at 10 mM 90% at 25 mM | Rat (liver) | [42] | |
37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 47% at 25 mM | Rat (liver) | [6] | |||
pH 8, 50 mM PO43− buffer 0.1 mM PLP, 10 mM Orn, 5 mM aKG | 26% at 10 mM | Rat (liver) | [14] | |||
(GABA) | 0.5 U OAT; 50 mM Orn | 26% at 25 mM | Rat (kidney) | [41] | ||
5-Aminovalerate | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 100% at 25 mM | Rat (liver) | [6] | ||
(δ-Aminovalerate) | 0.5 U OAT; 50 mM Orn | 15% at 25 mM | Rat (kidney) | [41] | ||
Competitive for Orn | pH 8, 0.05 mM PO43− buffer 0.01 mM PLP, 20 mM Orn, 10 mM aKG | 17.7 mM | Rat (liver) | [40] | ||
ε-Aminocaproate | 0.5 U OAT; 50 mM Orn | 6% at 25 mM | Rat (kidney) | [41] | ||
α-Ketoacids | ||||||
α-Ketovalerate | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 66% at 21 mM | Rat (liver) | [6] | ||
0.5 U OAT; 50 mM Orn | 38% at 25 mM | Rat (kidney) | [41] | |||
α-Ketoisocaproate | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 60% at 19 mM | Rat (liver) | [6] | ||
(Ketoleucine) | 0.5 U OAT; 50 mM Orn | 41% at 25 mM | Rat (kidney) | [41] | ||
α-Ketoisovalerate | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 45% at 22 mM | Rat (liver) | [6] | ||
0.5 U OAT; 50 mM Orn | 34% at 25 mM | Rat (kidney) | [41] | |||
α-Ketocaproate | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 18% at 15 mM | Rat (liver) | [6] | ||
0.5 U OAT; 50 mM Orn | 34% at 25 mM | Rat (kidney) | [41] | |||
α-Ketobutyrate | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 13% at 10 mM | Rat (liver) | [6] | ||
0.5 U OAT; 50 mM Orn | 27% at 25 mM | Rat (kidney) | [41] | |||
Polyamines | ||||||
Cadaverine | H2N-(CH2)5-NH2 | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 14% at 25 mM | Rat (liver) | [6] | |
0.5 U OAT; 50 mM Orn | 5.7% at 25 mM | Rat (kidney) | [41] | |||
Putrescine | H2N-CH2-CH2-CH2-CH2-NH2 | 37 °C, pH 7.1, 50 mM PO43− buffer 35 mM Orn, 3.75 mM aKG,K | 14% at 25 mM | Rat (liver) | [6] | |
pH 8, 50 mM PO43− buffer 0.1 mM PLP, 10 mM Orn, 5 mM aKG | No inhibition at 10 mM | Rat (liver) | [14] | |||
0.5 U OAT; 50 mM Orn | 3% at 25 mM | Rat (kidney) | [41] | |||
pH 8, 12.5 mM Tris-HCl buffer 0.025 mM PLP, 5 mM Orn, 2.5 aKG | No inhibition at 5 mM 8% at 10 mM | Rat (brain) | [23] | |||
Spermine | pH 8, 12.5 mM Tris-HCl buffer 0.025 mM PLP, 5 mM Orn, 2.5 aKG | 33% at 5 mM 56% at 10 mM | Rat (brain) | [23] | ||
pH 8, 50 mM PO43− buffer 0.1 mM PLP, 10 mM Orn, 5 mM aKG | No inhibition at 10 mM | Rat (liver) | [14] | |||
Spermidine | pH 8, 12.5 mM Tris-HCl buffer 0.025 mM PLP, 5 mM Orn, 2.5 aKG | 30% at 5 mM 48% at 10 mM | Rat (brain) | [23] | ||
Histamine | pH 8, 12.5 mM Tris-HCl buffer 0.025 mM PLP, 5 mM Orn, 2.5 aKG | 42% at 5 mM 50% at 10 mM | Rat (brain) | [23] | ||
Other inhibitors | ||||||
5-Fluoromethylornithine | Irreversible | 37 °C, pH 8, 50 mM PO43− buffer 175 mM Orn, 35 mM aKG | 70 µM | Rat (liver; partially purified) | [37] | |
8 U OAT, 37°C, pH 8, 0.05 mM PO43− buffer 0.1 mM PLP, 175 mM Orn, 35 mM aKG | 30 µM | Rat (liver) | [39] | |||
Not given | 11 ± 2 µM | [36] | ||||
S,S-5-Fluoromethylornithine | Not given | 2.4 ± 0.3 µM | [36] | |||
N-Acetylornithine | Competitive with Orn | pH 8, 0.05 mM PO43− buffer 0.01 mM PLP, 20 mM Orn, 10 mM aKG | 8.8 mM | Rat (liver) | [40] | |
pH 8, 12.5 mM Tris-HCl buffer 0.025 mM PLP, 5 mM Orn, 2.5 aKG | 24% at 2.5 mM 27% at 5 mM | Rat (brain) | [23] | |||
4-Aminohexynoate | Irreversible | 0.5 U OAT, 37 °C, 40 mM KPP0,020 mM PLP, 60 mM Orn, 21 mM aKG | Rat (liver) | [43] | ||
Gabaculine | Irreversible | 0.5 U OAT, 37 °C, 40 mM KPP 0,020 mM PLP, 60 mM Orn, 21 mM aKG | Rat (liver) | [43] | ||
2-aminooxyacetate | “almost complete” at 0.2 mM | Rat | [44] |
Organ | Tissue | Species | Activity | Unit | Reference |
---|---|---|---|---|---|
Eye | Neuroretina | Cat | 88.2 | mmol/kg dry wt/h | [70] |
Ox | 71 ± 17 | nmol/mg protein/30 min | [132] | ||
Optic nerve | Cat | 6.7 | mmol/kg dry wt/h | [70] | |
Tapetum | Cat | 26.7 | mmol/kg dry wt/h | [70] | |
Sclera | Cat | 5.36 | mmol/kg dry wt/h | [70] | |
Choroid | Cat | 17.4 | mmol/kg dry wt/h | [70] | |
Ox | 14 ± 5 | nmol/mg protein/30 min | [132] | ||
Retina | Rat | 174 ± 25 | nmol/mg protein/h | [133] | |
97 ± 9 | nmol/mg protein/30 min | [132] | |||
Ox | 119 ± 34 | nmol/mg protein/h | [133] | ||
Pig | 409 ± 50 | nmol/mg protein/h | [133] | ||
Dog | 159 | nmol/mg protein/h | [133] | ||
Chicken | 124 ± 16 | nmol/mg protein/h | [133] | ||
120 ± 20 | nmol/mg/h | [134] | |||
Turkey | 85 | nmol/mg protein/h | [133] | ||
Rana pipiens | 302 | nmol/mg protein/h | [133] | ||
Rana clamitans | 238 | nmol/mg protein/h | [133] | ||
Xenopus laevis | 392 ± 93 | nmol/mg protein/h | [133] | ||
Cyprinus carpio | 766 ± 57 | nmol/mg protein/h | [133] | ||
Pigment epithelium (iris epithelium) | Cat | 138 | mmol/kg dry wt/h | [70] | |
Rat | 988 ± 130 | nmol/mg protein/h | [133] | ||
Ox | 497 ± 89 | nmol/mg protein/h | [133] | ||
113 ± 24 | nmol/mg protein/30 min | [132] | |||
Pig | 2260 ± 630 | nmol/mg protein/h | [133] | ||
Dog | 602 ± 159 | nmol/mg protein/h | [133] | ||
Chicken | 1431 ± 535 | nmol/mg protein/h | [133] | ||
1670 ± 55 | nmol/mg/h | [134] | |||
Turkey | 1150 | nmol/mg protein/h | [133] | ||
Rana pipiens | 795 | nmol/mg protein/h | [133] | ||
Rana clamitans | 217 | nmol/mg protein/h | [133] | ||
Xenopus laevis | 171 ± 87 | nmol/mg protein/h | [133] | ||
Cyprinus carpio | 203 ± 51 | nmol/mg protein/h | [133] | ||
Vascular layer of the ciliary body | Cat | 63.0 | mmol/kg dry wt/h | [70] | |
Cornea | Cat | 8.11 | mmol/kg dry wt/h | [70] | |
Ox | 14 ± 9 | nmol/mg protein/30 min | [132] | ||
Lens | Cat | No | [70] | ||
Ox | No | [132] | |||
Brain | Frontal cortex | Rat | 1.45 ± 0.29 | mU/mg protein | [135] |
Occipital cortex | Rat | 1.38 ± 0.08 | mU/mg protein | [135] | |
Olfactory bulb | Rat | 1.23 ± 0.07 | mU/mg protein | [135] | |
Hippocampus | Rat | 1.33 ± 0.16 | mU/mg protein | [135] | |
Striatum | Rat | 0.95 ± 0.06 | mU/mg protein | [135] | |
Midbrain, thalamus | Rat | 1.17 ± 0.12 | mU/mg protein | [135] | |
Hypothalamus | Rat | 1.34 ± 0.10 | mU/mg protein | [135] | |
Pons, medulla oblongata | Rat | 0.85 ± 0.04 | mU/mg protein | [135] | |
Cerebellum | Rat | 0.90 ± 0.19 | mU/mg protein | [135] | |
Tractus opticus | Rat | 0.75 ± 0.10 | mU/mg protein | [135] | |
Spinal cord | Rat | 0.60 ± 0.07 | mU/mg protein | [135] | |
Liver | Rat | 179 | nmol/mg protein/h | [133] | |
242 ± 41 | nmol/mg protein/30 min | [132] | |||
Pig | 164 | nmol/mg protein/h | [133] | ||
Ox | 12 | nmol/mg protein/30 min | [132] | ||
Chicken | 174 ± 22 | nmol/mg protein/h | [133] | ||
150 ± 40 | nmol/mg/h | [134] | |||
Rana clamitans | 137 | nmol/mg protein/h | [133] | ||
Xenopus laevis | 161 ± 101 | nmol/mg protein/h | [133] | ||
Cyprinus carpio | 590 | nmol/mg protein/h | [133] |
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Ginguay, A.; Cynober, L.; Curis, E.; Nicolis, I. Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways. Biology 2017, 6, 18. https://doi.org/10.3390/biology6010018
Ginguay A, Cynober L, Curis E, Nicolis I. Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways. Biology. 2017; 6(1):18. https://doi.org/10.3390/biology6010018
Chicago/Turabian StyleGinguay, Antonin, Luc Cynober, Emmanuel Curis, and Ioannis Nicolis. 2017. "Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways" Biology 6, no. 1: 18. https://doi.org/10.3390/biology6010018
APA StyleGinguay, A., Cynober, L., Curis, E., & Nicolis, I. (2017). Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways. Biology, 6(1), 18. https://doi.org/10.3390/biology6010018