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oat

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Official Full Name
ornithine aminotransferase
Background
This gene encodes the mitochondrial enzyme ornithine aminotransferase, which is a key enzyme in the pathway that converts arginine and ornithine into the major excitatory and inhibitory neurotransmitters glutamate and GABA. Mutations that result in a deficiency of this enzyme cause the autosomal recessive eye disease Gyrate Atrophy. Alternatively spliced transcript variants encoding different isoforms have been described. Related pseudogenes have been defined on the X chromosome.
Synonyms
OAT; ornithine aminotransferase; ornithine aminotransferase, mitochondrial; gyrate atrophy; HOGA; ornithine aminotransferase precursor; GACR; OATASE; OKT; Ornithine aminotransferase (gyrate atrophy); Ornithine aminotransferase mitochondrial; Ornithine aminotransferase, mitochondrial precursor; Ornithine delta aminotransferase; Ornithine oxo acid aminotransferase; OTTHUMP00000020690; ornithine delta-aminotransferase; ornithine-delta-aminotransferase; ornithine-oxo-acid aminotransferase; ornithine--oxo-acid aminotransferase; DKFZp781A11155; organic anion transporter; slc22a6; zgc:77073; solute carrier family 22 member 6; ROAT1; zfOat; organic anion transporter 1; renal organic anion transporter 1

Ornithine-aminotransferase (Oat), or ornithine-transaminase, is an enzyme found in almost all eukaryotic organisms, from protozoans to humans, and from fungi to higher plants. It is highly conserved among these organisms. In humans, OAT deficiency causes a serious inherited disease, gyrate atrophy. This suggests that OAT plays a vital role in metabolism. Oat is a pyridoxal 5’-phosphate (PLP)-dependent mitochondrial matrix enzyme which catalyzes the interconversion of ornithine and α-ketoglutarate to L-glutamate semialdehyde, which cyclizes to Δ-pyrroline-5-carboxylate (P5C), and glutamate (Figure 1). Therefore, the importance of OAT may appear to be related to the roles of Glu in metabolism (bioenergetics, acid-base homeostasis, nitrogen flux), like the major enzymes involved in Glu metabolism (e.g., alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), and glutamate dehydrogenase (GDH)).

Figure 1. OAT Catalytic Mechanism

OAT and the development of mammals

Intestinal OAT plays the main role during development, as Arg synthesis requirements change from the fetus through weaning to adulthood. Conversion of Pro from maternal milk into Arg has been shown to be considerable in mouse and pig neonates, and there is evidence that human neonates also convert Pro into Arg by this pathway. The OAT requirement seems to be all the greater because growth is fast, and newborn mice with non-functional OAT die in a few days without an Arg supply. Milk in mammals is poor in Arg, and high net Arg production through the gut is required to sustain growth. However, in contrast to what is observed in mice neonates, loss of OAT activity in human newborns is non-lethal. This may be due to the faster relative growth rate observed in mice neonates, implying Arg requirements exceeding the availability of Arg in maternal milk.

Consequences of OAT deficiency: gyrate atrophy of the choroid and retina (GA)

OAT deficiency is the cause of a serious and disabling congenital metabolic disorder characterized by gyrate atrophy (GA) of the choroid and retina. So far, 65 OAT mutations have been identified according to the Human Gene Mutation Database. GA is an autosomal recessive disease clinically characterized by a childhood-onset visual disorder with myopia, followed by the development of night blindness, cataracts and progressive constriction of vision fields, resulting in blindness in the fourth to fifth decade. Although in the large majority of cases cognition is unimpaired, a few patients have been described with mental retardation. Biologically, patients with GA display an increase in plasma Orn concentration, and in some cases present an overflow cystinuria, ornithinuria and lysinuria when plasma Orn exceeds 400 μmol/L. It is noteworthy that the increase in plasma Orn occurs after the first 3 months of life.

OAT and hepatocellular carcinoma

The OAT gene is a β-catenin target gene that is highly expressed in hepatocellular carcinoma (HCC). Overexpression of the OAT gene is related to the activation of β-catenin signaling in the liver. Regulation of OAT gene-associated glutamine metabolism by β-catenin was suggested to be a contributing factor to carcinogenesis, which links the glutamine pathway to hepatocarcinogenesis. The Wnt/β-catenin signaling pathway is activated relatively early during liver regeneration, mostly through post-translational modifications. Once activated, β-catenin signaling drives the expression of target genes that are important for cell cycle progression and contributes to the initiation of the regeneration process. Among human cancers tightly linked to abnormal Wnt/β-catenin signaling, hepatoblastomas, uncommon malignant liver neoplasms occurring in infants and children, occur with the highest rate of β-catenin mutations. Among the signaling cascades that are deregulated in HCC, the Wnt/β-catenin signaling pathway plays a role in hepatic oncogenesis. And recent research showed that overexpression of the OAT gene in HCC and the ability to block the growth of HCC by OAT inhibitors support the role of OAT as a potential therapeutic target to inhibit HCC growth.

Although the major metabolic roles of OAT are now quite well understood, they do not explain all the reported observations—for example, the relationship between OAT mutation and the pathophysiology of gyrate atrophy remains poorly understood. Similarly, OAT involvement in pathologies such as cancer is also still needed to gain a better understanding.

References:

  1. Ginguay A, et al. Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways. Biology, 2017, 6(1):18.
  2. Lee H, et al. Ornithine aminotransferase vs. GABA aminotransferase. Implications for the design of new anticancer drugs. Medicinal Research Reviews, 2015, 35(2):286-305.
  3. Zigmond E, et al. Suppression of Hepatocellular Carcinoma by Inhibition of Overexpressed Ornithine Aminotransferase. Acs Medicinal Chemistry Letters, 2015, 6(8):840-4.
  4. Katagiri S, et al. OAT mutations and clinical features in two Japanese brothers with gyrate atrophy of the choroid and retina. Documenta Ophthalmologica Advances in Ophthalmology, 2014, 128(2):137.
  5. Dahmani R, Just P A. The Wnt/β-catenin pathway as a therapeutic target in human hepatocellular carcinoma. Clinics & Research in Hepatology & Gastroenterology, 2011, 35(11):709-713.