2.3.1.255 evolution RimI belongs to the general control non-repressible (GCN5)-related N-acetyltransferase (GNAT) family that carries a conserved Q/RxxGxG/A Ac-CoA-binding motif -, 755712 2.3.1.255 evolution there are seven known NAT types (NatA through NatG), each composed of one or more specific subunits and having specific substrates defined by the very first amino acid residue (serine, alanine, etc.) -, 758492 2.3.1.255 malfunction Aenzyme knockdown significantly reduces dendritic extension in cultured Purkinje cells 703852 2.3.1.255 malfunction enzyme knockdown causes a phenotype with lethality, growth retardation, bent axis and tails, abnormal eyes, and less pigmentation 756675 2.3.1.255 malfunction enzyme mutants show phenotypes with pleiotropic oogenesis, aberrant mitosis, egg chamber encapsulation defects, and nurse cell chromatin dispersion defects 756675 2.3.1.255 malfunction HYPK is a negative regulator for hNatA acetylation activity 757754 2.3.1.255 malfunction inactive Naa10 mutant S37Pw shows a phenotype with perinatal lethal disorder, hypotonia, global developmental delay, cryptorchidism, cardiac arrhythmias, skin laxity, dysmorphic features, hernias, and large fontanels. Naa10 mutant Y43S shows a phenotype with intellectual disability, facial dysmorphism, scoliosis, and long QT. Mutant R83C shows a phenootype with hypotonia, global developmental delay, dysmorphic features, autism spectrum disorder, epileptic encephalopathy, extrapyramidal signs, hypertension with left ventricular hypertrophy, thin corpus callosum, and progressive white matter loss. Mutations V107F and R116W cause phenotypes with severe global developmental delay with postnatal growth, skeletal anomalies, truncal hypotonia with hypertonia of the extremities, minor facial features, and behavioral anomalies. Mutation of residue F128 causes moderate to severe intellectually disability, feeding difficulties, eye anomalies, hypotonia, and developmental delay 756675 2.3.1.255 malfunction inhibition of hARD1/NAA10 autoacetylation by K136R mutation induces the drop of KAT activity, but not NAT activity 757723 2.3.1.255 malfunction knockdown and overexpression of Naa10p in osteosarcoma cells respectively leads to decreased and increased cell migratory/invasive abilities. Re-expression of Naa10p, but not of an enzymatically inactive mutant, relieves suppression of the invasive ability in vitro and metastasis in vivo imposed by Naa10p-knockdown. The matrix metalloproteinase (MMP)-2 is responsible for the Naa10p-induced invasive phenotype 756332 2.3.1.255 malfunction knockdown of acetyltransferase ARD1 significantly reduces the growth rate of human cancer cell lines. Furthermore, ARD1 knockdown induces apoptosis or sensitizes cells to drug induced apoptosis. Enzyme knockdown reduces the transcriptional activity of the beta-Catenin/TCF4 complex, downregulating cyclin D1 and thereby promoting G1-arrest and inhibition of cell proliferation of lung cancer cells 740340 2.3.1.255 malfunction knockdown of Naa10 in HeLa cells leads to apoptosis and sensitizes cells for daunorubicin-induced apoptosis 740508 2.3.1.255 malfunction measuring the different time points of gene expression upon Naa10 siRNA treatment, NTN1 and its receptor UNC5B are found to be the most dramatically overexpressed among the genes involved in morphogenesis -, 758388 2.3.1.255 malfunction measuring the different time points of gene expression upon Naa10 siRNA treatment, NTN1 and its receptor UNC5B are found to be the most dramatically overexpressed among the genes involved in morphogenesis. Analysis of upregulated genes in Naa10 stably knocked down H1299 cell line, overview 758388 2.3.1.255 malfunction mutation ard1::HIS3 leads to a defect in transcription of a-specific genes, but permits expression of the information resident at HML. The mutant shows a phenotypes with reduced viability and sensitivity to heat shock and salt, it fails to enter stationay phase, it shows a lack of glycogen accumulation, a sporulation defect, poor mating, and fails to undergo meiosis. The mutant nat1-5::LEU;ard1 is inable to sporulate, has slow growth, reduced mating, inhibited sporulation, and impaired resistance to heat shock. It fails G1 arrest, shows a partial depression of HML, and fails to accumulate storage. yNaa10 deficiency leads to a growth defect, sensitivity to caffeine and cycloheximide, impaired resistance to heat shock, and decreased mating efficiency -, 756675 2.3.1.255 malfunction mutations in N-terminal acetyltransferase Naa10 are the cause of Ogden Syndrome 741085 2.3.1.255 malfunction mutations in the X-linked gene NAA10 cause Ogden Syndrome (also known as NAA10-related syndrome), which affects numerous aspects of development. Wide-ranging developmental defects are observed in humans with mutations in NAA10 and NAA15 -, 758492 2.3.1.255 malfunction NAA10 germline variants are found in patients with the X-linked lethal Ogden syndrome, and in other familial or de novo cases with variable degrees of developmental delay, intellectual disability (ID) and cardiac anomalies. A R83H missense variant in NAA10 is detected by whole exome sequencing in two unrelated boys with intellectual disability, developmental delay, ADHD like behaviour, very limited speech and cardiac abnormalities. Phenotypes, overview. Mutant NAA10-R83H has a reduced monomeric catalytic activity, likely due to impaired enzyme-acetyl-CoA binding 756298 2.3.1.255 malfunction naa10 morphants display increased lethality, growth retardation and developmental abnormalities like bent axis, abnormal eyes and bent tails 735797 2.3.1.255 malfunction NAA10 variants have been found in patients with an X-linked developmental disorder called Ogden syndrome in its most severe form and, in other familial or de novo cases, with variable degrees of syndromic intellectual disability (ID) affecting both sexes. The mutant NAA10-V111G has a reduced stability and 85% reduced monomeric catalytic activity, while catalytic NatA function remains unaltered. The syndromic cases may also require a degree of compromised NatA function. The Naa10-V111G phenotype shows mild/moderate non-syndromic intellectual disability, and delayed motor and language development, but normal behavior without autistic traits. The blood leukocyte X-inactivation pattern is within normal range (80/20) 756297 2.3.1.255 malfunction oligomerization results in the loss of KAT activity 757723 2.3.1.255 malfunction overexpression of gene daf-31 causes an increased lifespan in daf-2 mutant enhancing reproduction, while daf-31 knockdown by siRNA causes a decreased lifespan -, 756675 2.3.1.255 malfunction overexpression of Naa10 in mice results in the delayed closure of calvarial fontanels and reduced bone density, osteoblast surfaces and mRNA levels of the osteoblastogenic genes in calvaria. In contrast, Naa10 deficient mice display calvarial and femoral bone development to a greater extent on postnatal day 3 -, 756675 2.3.1.255 malfunction reduced enzyme levels result in pleiotropic oogenesis defects including abnormal cyst encapsulation, desynchronized cystocyte division, disrupted nurse cell chromosome dispersion, and abnormal chorion patterning. Loss of Ard1 affects cell survival/proliferation and is lethal for the animal 719333 2.3.1.255 malfunction several X-linked NAA10 variants have been associated with genetic disorders. A NAA10 variant I72T with impaired acetyltransferase activity causes developmental delay, intellectual disability, and hypertrophic cardiomyopathy. Genotype-phenotype correlations for NAA10 variants, overview 756642 2.3.1.255 malfunction the ARD1 null mutation leads to impaired growth in bloodstream-form cells and reduced differentiation to insect-stage cells 756675 2.3.1.255 malfunction the naa10 knockout mutant naa10-1 shows growth retardation in vegetative stage, abortion of embryogenesis, and drought-adapted root morphology, the mutation is lethal. A knockout of naa15 causes the same phenotype 756675 2.3.1.255 metabolism ARD1 variants have different effects on hypoxia-inducible factor-1alpha stability and acetylation 739977 2.3.1.255 metabolism Naa10 activates and/or amplifies the transcriptional activity of beta-catenin/TCF transcriptional activity thereby stimulating cyclin D1 and c-Myc expression leading to inhibition of p21WAF1/CIP1 and promoting the G1/S cell cycle transition. Naa10 is essential for the activation of caspase-2/-3/-7 and -9 in HeLa cells after doxorubicin stimulation 740508 2.3.1.255 metabolism NAT1 and ARD1 proteins function together to catalyze the N-terminal acetylation of a subset of yeast proteins 740373 2.3.1.255 metabolism the enzyme is involved in the co-translational N-terminal protein modification process, overview -, 758492 2.3.1.255 additional information NatA homology modeling. Residue V111 is located towards the end of the beta5 strand, and a valine in this position is highly conserved in NAA10 homologues as well as in several other NAT catalytic subunits for which crystal structures have been solved. The side chain of V111 is forming a hydrophobic pocket together with Y145, M147, L119 and L109. It is also in close proximity to the sulfur group of acetyl-CoA, which seems to indicate a role for V111 in positioning of acetyl-CoA. A glycine in this position will not cause any steric clashes, but loss of the more bulky hydrophobic side chain of valine may possibly cause structural alterations affecting protein stability or AcCoA binding 756297 2.3.1.255 additional information structure comparison, wild-type NAA10 and mutant NAA10-R83H from the human NatA complex (PDB ID 6C9M) are compared with the structure of NAA10 from the Schizosaccharomyces pombe NatA complex (PDB ID 4KVM) 756298 2.3.1.255 additional information structure modeling and molecular docking of RimI, docking of the structure model of MtRimI-Ala-Arg-Tyr-Phe-Arg-Arg (ARYFRR) complex using the crystal structure of the RimI and bisubstrate from Salmonella typhimurium strain LT2 (PDB 2CNM) as template, overview. Structure comparison of wild-type MtRimI and mutant MtRimIC21A4-153 -, 755712 2.3.1.255 additional information the NAT activity is highest for the monomeric enzyme, about 2fold higher compared to the oligomeric enzyme and about 20% higher compared to the dimeric enzyme 757723 2.3.1.255 additional information the NatA enzyme complex is composed of the subunits Naa10 and Naa15. ScNaa15 has a high degree of structural conservation with SpNaa15 and hNaa15 structures 758492 2.3.1.255 additional information the NatA enzyme complex is composed of the subunits Naa10 and Naa15. ScNaa15 has a high degree of structural conservation with SpNaa15 and hNaa15 structures, and ScNaa10 is similarly and completely locked into a cradle by the surrounding Naa15 helices. ScNaa50 has a robust interaction with ScNatA that is maintained even in high salt concentrations (1 M NaCl) -, 758492 2.3.1.255 additional information the NatA enzyme complex is composed of the subunits Naa10 and Naa15. ScNaa15 has a high degree of structural conservation with SpNaa15 and hNaa15 structures. SpNaa50 has a robust interaction with SpNatA that is maintained even in high salt concentrations (1 M NaCl) -, 758492 2.3.1.255 additional information Trypanosoma cruzi NatA protein complex consists of one catalytic subunit and one predicted auxiliary subunit. TcNatC (EC 2.3.1.256) and TcNatA complex subunits interact in vivo and in vitro -, 757472 2.3.1.255 physiological function ARD1 is essential for viability in mammalian and insect-stage Trypanosoma brucei cells -, 740977 2.3.1.255 physiological function arrest defective 1 (ARD1), also known as N(alpha)-acetyltransferase 10 (NAA10) is originally identified as an N-terminal acetyltransferase (NAT) that catalyzes the acetylation of N-termini of newly synthesized peptides. Mammalian ARD1/NAA10 also plays a role as lysine acetyltransferase (KAT) that posttranslationally acetylates internal lysine residues of proteins. ARD1/NAA10 is the only enzyme with both NAT (EC 2.3.1.255) and KAT (EC 2.3.1.48) activities. NATs acetylate N-terminal residues of newly synthesized proteins from ribosomes in an irreversible manner. N-terminal acetylation is known to be closely related to protein stability, interaction, and localization. lysine acetylation catalyzed by KATs is reversibly regulated by lysine deacetyltransferases (KDACs) that remove acetyl groups from lysine residues in proteins. While acetylation neutralizes the positive charge on lysine residues, deacetylation recovers it, thereby causing a change in electronic and conformational properties of proteins. Acetylation and deacetylation of lysine residues serve as the switches that turn-on and turn-off the cellular signal pathways and regulate diverse biological events. Any unbalance between lysine acetylation and deacetylation results in the improper regulation of biological processes and may cause various types of human diseases such as cancer and neurodegeneration 757723 2.3.1.255 physiological function enzyme Daf-31 regulates the transcriptional activity of DAF-16, the FOXO transcription factor. Mutant daf-31(m655) leads to developmental larval arrest, fat accumulation, formation of dauer-like larvae under starvation conditions, and decreased lifespan, and the mutant lacks SDS-resistance and cannot resume development and reproduction after food re-providing -, 756675 2.3.1.255 physiological function enzyme variant ARD1131 has no influence on cyclin D1 expression and cell growth 736273 2.3.1.255 physiological function hNatA significantly enhances the catalytic efficiency of hNatE (EC 2.3.1.258). The hNatE complex comprises subunits Naa10 and Naa15 (NatA) and Naa50. HYPK binding to hNatE largely nullifies this effect 757754 2.3.1.255 physiological function importance of NAA10 catalytic activity in human development. The potential role of NAA10 varies depending on transcriptional levels in different tissues and embryonic stages during development 756675 2.3.1.255 physiological function importance of NAA10 catalytic activity in mouse development. The potential role of NAA10 varies depending on transcriptional levels in different tissues and embryonic stages during development. Naa10 homologue Naa11 has a role in the cellular differentiation process while Naa10 has a role in the cellular proliferation process. The differential expression pattern of Naa10 and Naa11 suggests that Naa11 is complementary to Naa10 at least in the mice and that its biological role can be important in spermiogenesis or cellular processes -, 756675 2.3.1.255 physiological function importance of NAA10 catalytic activity in mouse development. The potential role of NAA10 varies depending on transcriptional levels in different tissues and embryonic stages during development. Naa10 homologue Naa11 has a role in the cellular differentiation process while Naa10 has a role in the cellular proliferation process. The differential expression pattern of Naa10 and Naa11 suggests that Naa11 is complementary to Naa10 at least in the mice and that its biological role can be important in spermiogenesis or cellular processes. Naa10 is known to regulate cellular processes, and its effects are not only catalyzed through its major activity as a NAT but also through the N-epsilon-acetylation of several proteins. The N-epsilon-acetyl-activity of Naa10 requires auto-acetylation. This requirement is similar to that of other acetyltransferases, which acetylate themselves for their catalytic and functional activities. Naa10 plays an important role in osteoblast differentiation and the early phases of bone formation. Naa10 counteracts HDAC6 by acetylating alpha-tubulin, thereby promoting MT stability for dendritic development -, 756675 2.3.1.255 physiological function N-alpha-acetyltransferase 10 (Naa10) is the catalytic subunit of N-acetyltransferase A (NatA), it catalyzes N-alpha-acetylation, epsilon-acetylation, as well as autoacetylation. The alpha (N-terminal) acetyltransferase functions as a major modulator of cell growth and differentiation. Potential function of Naa10 in cell morphogenesis. Negative regulation of Naa10 towards NTN1 and its receptor UNC5B are detected upon treatment of all-trans retinoid acid, used to induce morphological differentiation. UNC-5 Homolog B (UNC5b), a dependence receptor of netrin-1, plays an essential role in mediating the repulsive effect of axonal migration and blood vessel formation through association with its ligand netrin-1 (NTN1). In addition, UNC5B has also been indicated as a putative tumor suppressor gene in numerous cancers 758388 2.3.1.255 physiological function N-alpha-acetyltransferase 10 (Naa10) is the catalytic subunit of N-acetyltransferase A (NatA), it catalyzes N-alpha-acetylation, epsilon-acetylation, as well as autoacetylation. The alpha (N-terminal) acetyltransferase functions as a major modulator of cell growth and differentiation. Potential function of Naa10 in cell morphogenesis. Negative regulation of Naa10 towards NTN1 and its receptor UNC5B are detected upon treatment of all-trans retinoid acid, usedto induce morphological differentiation. UNC-5 Homolog B (UNC5b), a dependence receptor of netrin-1, plays an essential role in mediating the repulsive effect of axonal migration and blood vessel formation through association with its ligand netrin-1 (NTN1). In addition, UNC5B has also been indicated as a putative tumor suppressor gene in numerous cancers -, 758388 2.3.1.255 physiological function N-alpha-acetyltransferase 10 protein (Naa10p) mediates N-terminal acetylation of nascent proteins. It promotes metastasis by stabilizing matrix metalloproteinase-2 protein in human osteosarcomas via its N-terminal acetylation activity. Oncogenic role of Naa10p, overview. Higher NAA10 transcripts are observed in metastatic osteosarcoma tissues compared to non-metastatic tissues and are also correlated with a worse prognosis of patients. Naa10p is directly associated with MMP-2 protein through its acetyltransferase domain and maintains MMP-2 protein stability via NatA complex activity. MMP-2 expression levels are also significantly correlated with Naa10p levels in osteosarcoma tissues. Function of Naa10p in the regulation of cell invasiveness by preventing MMP-2 protein degradation that is crucial during osteosarcoma metastasis. Naa10p promotes migratory/invasive abilities of osteosarcoma cells, it regulates cell invasion of the osteosarcoma cell lines 756332 2.3.1.255 physiological function N-terminal acetylation (NTA) is among the most widespread co-translational modifications found in eukaryotic proteins. NTA is carried out by N-terminal acetyltransferases (NATs), which catalyze the transfer of an acetyl moiety from acetyl coenzyme A to the N-terminal amino group of the nascent polypeptides as they emerge from the ribosome. NTA is an irreversible protein modification -, 758492 2.3.1.255 physiological function N-terminal acetylation (NTA) is among the most widespread co-translational modifications found in eukaryotic proteins. NTA is carried out by N-terminal acetyltransferases (NATs), which catalyze the transfer of an acetyl moiety from acetyl coenzyme A to the N-terminal amino group of the nascent polypeptides as they emerge from the ribosome. NTA is estimated to affect up to 90% of human proteins and influences their folding, localization, complex formation, and degradation, along with a variety of cellular functions ranging from apoptosis to gene regulation. NTA is an irreversible protein modification 758492 2.3.1.255 physiological function N-terminal acetylation catalyzed by NATs is one of the most common protein modifications in eukaryotes, affecting about 80% human proteins. In general, NATs acetylate N-terminal residues of newly synthesized proteins from ribosomes in an irreversible manner. N-terminal acetylation is known to be closely related to protein stability, interaction, and localization. Human ARD1/NAA10 expanded its' role to lysine acetyltransferase (KAT) that post-translationally acetylates internal lysine residues of proteins. Size-exclusion analysis reveals that most recombinant hARD1/NAA10 forms oligomers While oligomeric recombinant hARD1/NAA10 loses its ability for lysine acetylation, its monomeric form clearly exhibited lysine acetylation activity in vitro. In contrast to N-terminal acetylation, lysine acetylation catalyzed by KATs is reversibly regulated by lysine deacetyltransferases (KDACs) that remove acetyl groups from lysine residues in protein. hARD1 regulates a wide range of cellular functions, including cell cycle, apoptosis, migration, stress response, and differentiation. NAT and KAT activity might be independently regulated, relying on the interaction partners 757723 2.3.1.255 physiological function N-terminal acetylation is a common protein modification in human cells and is catalysed by N-terminal acetyltransferases (NATs), mostly cotranslationally. The NAA10-NAA15 (NatA) protein complex is the major NAT, responsible for acetylating about 40% of human protein. Naa15 is the NatA auxiliary subunit 756298 2.3.1.255 physiological function Naa10 is crucial for cell growth and sporulation -, 756675 2.3.1.255 physiological function Nalpha-acetylation is a naturally occurring irreversible modification of N-termini of proteins catalyzed by Nalpha-acetyltransferases (NATs) -, 758368 2.3.1.255 physiological function RimI, an Nalpha-acetyltransferase in Mycobacterium tuberculosis, is responsible for the acetylation of the alpha-amino group of the N-terminal residue in the ribosomal protein S18. Protein acetylation may be correlated with the pathogenesis of tuberculosis -, 755712 2.3.1.255 physiological function TcNatC/TcNatA proteins carry out their function independently of each other as suggested in other organisms and they may have specific functions depending on the parasite life cycle stage. But the proteins may also have other functions independent of the NAT-activity as suggested in other species -, 757472 2.3.1.255 physiological function the ARD1-NAT1 complex has acetyltransferase activity against microtubules in dendrites and regulates dendritic arborization in neuronal cells 703852 2.3.1.255 physiological function the enzyme acts in complex with the NATH protein and catalyzes cotranslational acetylation of protein N-termini 740340 2.3.1.255 physiological function the enzyme controls osteoblast differentiation and bone formation as a feedback regulator of Runt-related transcription factor 2 741046 2.3.1.255 physiological function the enzyme is essential for normal development and viability of zebrafish 735797 2.3.1.255 physiological function the enzyme is involved in ribosome synthesis. Optimal NatA function is important to the cooperative function of Brx1 with Ebp2 in 60S ribosomal subunit biogenesis 740179 2.3.1.255 physiological function the NAA10-NAA15 (NatA) protein complex is an N-terminal acetyltransferase responsible for acetylating about of eukaryotic proteins 756297 2.3.1.255 physiological function the NAA10-NAA15 complex (NatA) is an N-terminal acetyltransferase that catalyzes N-terminal acetylation of about 40% of all human proteins. N-terminal acetylation has several different roles in the cell, including altering protein stability and degradation, protein localization and protein-protein interactions 756642