The mitochondrial respiratory chain consists of 5 enzyme complexes that are responsible for ATP generation. The paradigm of the electron transport chain as discrete enzymes diffused in the inner mitochondrial membrane has been replaced by the solid state supercomplex model wherein the respiratory complexes associate with each other to form supramolecular complexes. Defects in these supercomplexes, which have been shown to be functionally active and required for forming stable respiratory complexes, have been associated with many genetic and neurodegenerative disorders demonstrating their biomedical significance. In this review, we will summarize the functional and structural significance of supercomplexes and provide a comprehensive review of their assembly and the assembly factors currently known to play a role in this process.
Adenosine Triphosphate ; metabolism ; Arylamine N-Acetyltransferase ; metabolism ; Cardiolipins ; metabolism ; Electron Transport ; Humans ; Mitochondria ; enzymology ; metabolism ; Multienzyme Complexes ; chemistry ; metabolism

Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response.
Antitubercular Agents/blood/*therapeutic use ; Arylamine N-Acetyltransferase/genetics ; Chromatography, High Pressure Liquid ; Drug Monitoring ; Humans ; Nutritional Status ; Pharmacogenetics ; Tandem Mass Spectrometry ; Tuberculosis/*drug therapy

OBJECTIVETo explore how arylamine N-acetyltransferases (NATs) is related to cell apoptosis.

METHODSNAT activity in apoptotic HepG2 cells was measured using high performance liquid chromatography (HPLC); the apoptosis rate of HepG2 cells acted upon by an NAT inhibitor was measured using flow cytometry.

RESULTSNAT activity was lowered in apoptotic HepG2 cells; apoptosis rate induced by camptothecin (CAM) increased after inhibition of NAT activity in HepG2 cells.

CONCLUSIONNAT can inhibit apoptosis in HepG2 cells.

Apoptosis ; drug effects ; Arylamine N-Acetyltransferase ; antagonists & inhibitors ; metabolism ; Camptothecin ; administration & dosage ; Cells, Cultured ; Dose-Response Relationship, Drug ; Hepatocytes ; cytology ; drug effects ; enzymology ; Humans

Adolescent ; Adult ; Antitubercular Agents ; adverse effects ; Arylamine N-Acetyltransferase ; genetics ; Chemical and Drug Induced Liver Injury ; Female ; Humans ; Isoniazid ; adverse effects ; Male ; Middle Aged ; Polymorphism, Genetic ; Young Adult

OBJECTIVEN-acetyltransferase 2 (NAT2) and cytochrome P450 2EI (CYP2E1) play a crucial role in the drug metabolic process. The aim of this study was to understand the genotype and phenotype polymorphisms of NAT2 and CYP2E1 in the Han Chinese pediatric population in order to provide a theoretical basis for individualized drug treatment.

METHODSA total of 341 (211 males and 130 females) randomly sampled Han Chinese children, aged from 2 months to 14 years, were enrolled in this study. Genotyping was carried out by PCR method, and metabolic phenotypes were identified.

RESULTSIn this study population, wild genotype was found as a major genotype in seven SNPs of NAT2, rs1801279, rs1041983, rs1801280, rs1799929, rs1799930, rs1208 and rs1799931. The frequency of NAT2 fast metabolism was highest (61.3%), followed by middle to slow metabolism (34.1%). Wild genotype also predominated in the four SNPs of CYP2E1 (rs2031920, rs3813867, rs6413432 and rs72559720) named as CYP2E1*5, *6 and *2, with a frequency of 61.3%, 60.1% and 99.4% respectively. As the relationship between CYP2E1 genotype and phenotype was unknown, phenotyping of CYP2E1 was not done.

CONCLUSIONSThe important SNPs of NAT2 and CYP2E1 are predominantly wild genotype in the Han Chinese pediatric population. Fast metabolic phenotype predominates in important SNPs of NAT2.

Adolescent ; Arylamine N-Acetyltransferase ; genetics ; Child ; Child, Preschool ; China ; ethnology ; Cytochrome P-450 CYP2E1 ; genetics ; Female ; Genotype ; Humans ; Infant ; Infant, Newborn ; Male ; Phenotype ; Polymorphism, Single Nucleotide

OBJECTIVESTo study the possible relationship between CYP1A1, NAT2 genetic polymorphisms and the susceptibility of prostate cancer.

METHODSForty-eight patients with prostate cancer and 112 healthy cases were selected as the control randomly. NAT2 and CYP1A1 gene polymorphisms were analysed with the methods of PCR-RFLP, ASA and real-time fluorescence Light-Cycler. The difference of frequency between the patients and the controls was compared.

RESULTSAmong prostate cancer patients and their matched controls, the frequencies of alleles and genotypes were significantly different with Ile-Val gene Polymorphisms (P < 0.05), in which the frequency of the allele G and GG genotypes were significantly higher than those in their matched controls with an odds ratio of 1.59 and 3.06(P < 0.05), respectively; No significant differences of the frequencies of the MspI alleles and genotypes were found between the patients with prostate cancer and the matched controls(P > 0.05). No significant differences of NAT2 slow acetylator genotype frequency were found between the controls and prostate cancer patients (P > 0.05).

CONCLUSIONSThe CYP1A1 Ile-Val gene polymorphisms might be associated with the occurrence of prostate cancer, while MspI gene polymorphisms and NAT2 slow acetylator genotype might not be associated with the occurrence of prostate cancer.

Adult ; Aged ; Arylamine N-Acetyltransferase ; genetics ; Cytochrome P-450 CYP1A1 ; genetics ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic ; Prostatic Neoplasms ; genetics

OBJECTIVETo study the possible relationship between genetic polymorphism of N-acetyltransferase 2 (NAT2) and susceptibility to hepatocellular carcinoma.

METHODSGenetic polymorphisms of the four NAT2 genes in 78 patients with hepatocellular carcinoma and 112 healthy controls were analyzed by means of real-time fluorescence light-Cycler. The difference in frequencies between the hepatocellular carcinoma patients and the controls were compared.

RESULTSThe significant difference in slow acetylation genotype frequency was found between the controls and the hepatocellular carcinoma patients who were smokers (17.9% vs 37.5%, x(2)= 4.67, P<0.05) resulting in increased by 2.76 times the risk for hepatocellular carcinoma, but no evident difference between the controls and hepatocellular carcinoma patients who were non-smokers.

CONCLUSIONThe smokers with slow acetylation genotype of N-acetyltransferase 2 may be the population with high risk for hepatocellular carcinoma.

Acetylation ; Adult ; Aged ; Arylamine N-Acetyltransferase ; genetics ; Carcinoma, Hepatocellular ; genetics ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; Liver Neoplasms ; genetics ; Male ; Middle Aged ; Polymorphism, Genetic ; Smoking ; genetics

Treatment of latent tuberculosis infection remains an important goal of global TB eradication. To this end, targets that are essential for intracellular survival of Mycobacterium tuberculosis are particularly attractive. Arylamine N-acetyltransferase (NAT) represents such a target as it is, along with the enzymes encoded by the associated gene cluster, essential for mycobacterial survival inside macrophages and involved in cholesterol degradation. Cholesterol is likely to be the fuel for M. tuberculosis inside macrophages. Deleting the nat gene and inhibiting the NAT enzyme prevents survival of the microorganism in macrophages and induces cell wall alterations, rendering the mycobacterium sensitive to antibiotics to which it is normally resistant. To date, NAT from M. marinum (MMNAT) is considered the best available model for NAT from M. tuberculosis (TBNAT). The enzyme catalyses the acetylation and propionylation of arylamines and hydrazines. Hydralazine is a good acetyl and propionyl acceptor for both MMNAT and TBNAT. The MMNAT structure has been solved to 2.1 Å resolution following crystallisation in the presence of hydralazine and is compared to available NAT structures. From the mode of ligand binding, features of the binding pocket can be identified, which point to a novel mechanism for the acetylation reaction that results in a 3-methyltriazolo[3,4-a]phthalazine ring compound as product.
Acetyltransferases ; metabolism ; Arylamine N-Acetyltransferase ; chemistry ; genetics ; metabolism ; Catalysis ; Catalytic Domain ; Crystallization ; Mycobacterium ; enzymology ; metabolism ; Mycobacterium marinum ; enzymology ; Mycobacterium tuberculosis ; enzymology ; genetics ; metabolism ; Protein Binding

OBJECTIVETo study the relationship between genetic polymorphism of NAT2 and susceptibility to bladder cancer.

METHODSNAT2 genotypes were determined by PCR-RFLP method in 69 patients with bladder transitional cell carcinoma and 88 healthy controls.

RESULTSThe frequency of NAT2 slow genotypes was 26.1% (18/69) in patients compared with 14.8% (13/88) in controls (P < 0.05). Bladder cancer risk in patients with NAT2 slow genotypes was 2 fold as high as that in patients with NAT2 rapid genotypes. When NAT2 rapid genotypes/non-smoker were used as reference, bladder cancer risk increased to 5.8-fold (P < 0.05). Among the smokers with PY higher than 10, the patients showed a higher frequency of NAT2 slow genotype than controls (P < 0.05). It was also shown that the patients with slow NAT2 genotypes were more likely to have high grade tumor (P < 0.05) and advanced stage tumor (P < 0.01).

CONCLUSIONThe results suggest that NAT2 genetic polymorphism is associated with bladder cancer susceptibility. People with NAT2 slow genotype have higher bladder cancer risk.

Arylamine N-Acetyltransferase ; genetics ; Carcinoma, Transitional Cell ; enzymology ; genetics ; pathology ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Smoking ; Urinary Bladder Neoplasms ; enzymology ; genetics ; pathology

OBJECTIVETo study the possible relationship between polymorphic N-acetyltransferase 2 (NAT2) acetylator status and antituberculosis drug-induced hepatotoxicity and to elucidate the molecular mechanism of antituberculosis drug-induced hepatotoxicity.

METHODSBlood samples from 101 tuberculosis cases with antituberculosis drug-induced hepatotoxicity and from 107 tuberculosis without antituberculosis drug-induced hepatotoxicity were collected for a case-control study. DNA of the subjects was extracted and amplified by polymerase chain reaction (PCR). The single nucleotide polymorphisms of NAT2 were determined by direct PCR sequencing. The genotype frequencies were compared between cases and controls by χ(2) test, using SPSS 12.0 software, and the association between the disease and genotypes was analyzed.

RESULTSAmong the 101 patients with antituberculosis drug-induced liver injury, 36 patients (35.6%) were found with 282 T/T, 12 (11.9%) with 590 A/A, and 48 (47.5%) with 857 G/A or A/A. However, among the 107 controls, 9 patients (8.4%) were found with 282 T/T, 3 (2.8%) with 590 A/A, and 33 (33.8%) with 857 G/A or A/A. The patients with 282 T/T, 590 A/A, or 857 G/A or A/A genotype had a higher risk of antituberculosis drug-induced hepatotoxicity than those with 282 C/C or C/T, 590 G/G or G/A, or 857 G/G, and the OR values were 6.03 (95%CI: 2.88 - 12.62; χ(2) = 22.73, P < 0.05), 4.67 (95%CI: 1.42 - 15.44; χ(2) = 6.40, P < 0.05) and 2.03 (95%CI: 1.16 - 3.57; χ(2) = 6.08, P < 0.05) respectively. There were 40 patients with slow acetylator (39.6%) in cases with hepatotoxicity and 13 with slow acetylator (12.2%) in controls without hepatotoxicity. Patients with slow acetylator genotype (OR = 4.74, 95% CI = 2.42 - 9.28; χ(2) = 20.62, P < 0.05) had a significantly higher risk of antituberculosis drug-induced hepatotoxicity than those with rapid or intermediate acetylator genotypes. Among the cases, 19.8% (20/101) were found with NAT2(*)6A/7B, and 11.9% (12/101) with NAT2(*)6A/6A, whereas among the controls, 2.8% (3/107) were found with NAT2(*)6A/7B, and 2.8% (3/107) with NAT2(*)6A/6A respectively, the patients with NAT2(*)6A/7B and NAT2(*)6A/6A had a much higher risk of antituberculosis drug-induced hepatotoxicity, and the OR values were 8.40 (95%CI: 2.85 - 24.73; χ(2) = 14.90, P < 0.05) and 4.67 (95%CI: 1.42 - 15.44; χ(2) = 6.40, P < 0.05) respectively.

CONCLUSIONPerhaps, the slow acetylation genotypes of NAT2 were the main risk factors of developing antituberculosis drug-induced hepatotoxicity.

Adult ; Antitubercular Agents ; adverse effects ; Arylamine N-Acetyltransferase ; genetics ; Case-Control Studies ; Chemical and Drug Induced Liver Injury ; etiology ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Tuberculosis ; drug therapy ; genetics ; Young Adult