Publicação

Pentose phosphate pathway in health and disease: from metabolic dysfunction to biomarkers

Detalhes bibliográficos
Resumo:	The Pentose Phosphate Pathway (PPP) fulfils two unique functions: (i) the formation of ribose-5-phosphate (R5P) for the synthesis of nucleotides, RNA and DNA, supporting cell growth and proliferation; and (ii) the formation of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH). NADPH carries chemical energy in the form of reducing power, being essential to the cellular oxidative defense system and is also the universal reducing agent in many anabolic pathways, such as cholesterol and lipid synthesis and fatty acids chain elongation. The PPP comprises two separate branches: (i) an oxidative, non-reversible branch, and (ii) a non-oxidative, reversible branch. The oxidative branch primarily depends on glucose 6-phosphate dehydrogenase (G6PD), whereas transaldolase (TALDO) is the rate-limiting enzyme for the non-oxidative branch. Although the oxidative branch of the PPP is recognized as the source of NADPH and R5P, the overall contribution of the non-oxidative branch to metabolism and cell survival is poorly understood. Metabolism of glucose through the PPP influences the development of diverse pathologies. Deficiency of the PPP enzyme G6PD represents the most common genetic defect in humans and leads to NADPH depletion in red blood cells (RBC), predisposing to oxidative stress-induced hemolytic anemia. Recently, two new defects in the PPP were described: ribose-5-phosphate isomerase (RPI) deficiency and transaldolase (TALDO) deficiency. The first defect is associated with progressive leukoencephalopathy and mild peripheral neuropathy. The metabolic profile of the disease is associated with elevated levels of ribitol and arabitol in the brain, as showed by magnetic resonance spectroscopy (MRS), urine, plasma and cerebrospinal fluid (CSF). In contrast, TALDO deficiency is associated with liver symptoms, while other organs are affected to a variable degree. The metabolic phenotype of the disease is characterized by increased urinary concentrations of the polyols: erythritol, arabitol, ribitol, sedoheptitol, perseitol and the sugars: sedoheptulose and mannoheptulose, as well as sedoheptulose-7-phosphate. The profound influence of TALDO on NADPH levels, mitochondrial dysfunction and oxidative stress is ascribed to the blocked recycling of R5P to glucose 6-phosphate (G6P) and to the proposed linkage to aldose reductase (AR) that converts the accumulated C5-sugar phosphates to C5-polyols at the expense of NADPH. Mitochondrial dysfunction associated to TALDO deficiency leads to liver disease progressing from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Therefore, TALDO deficiency can account for liver disease of variable severity. The diagnosis of the PPP deficiencies is possible by biochemical evaluation of polyols’ and sugars’ profiles in body fluids. Abnormal concentrations of these compounds occur in a number of pathological conditions such as diabetes mellitus, renal and liver disease and several inborn errors of carbohydrate metabolism, such as galactosemia. Therefore, it is necessary to take into account the variability of metabolic profiles and to understand their meaning. Along the thesis, it is our goal to revise the metabolic pathway of pentose phosphates and its implication in the associated disease states. Furthermore, the development and validation of the analytical methods (GC-FID and GC-MS) will be presented and discussed. We will also present our preliminary results upcoming from two separated studies, focused on the characterization of the PPP intermediate metabolites profile in (1) pre-selected cases with unexplained hepatosplenomegaly and/or liver dysfunction in a pediatric population; and (2) in adult patients with liver dysfunction (NAFLD or AFLD). We hope to find new biomarkers and metabolic signs which may open new perspectives of research for better understanding liver dysfunction. Interesting data is described, in the pediatric population, where a patient with an isolated sedoheptulokinase (SHPK) deficiency is reported. All the subsequent studies, some still in course, seem to confirm this new defect in the PPP. In the adult population our findings point to the putative importance of polyols as possible biomarkers of liver dysfunction progression.
Autores principais:	Ramos, Rúben José Jesus Faustino
Assunto:	Pentose Phosphate Pathway Ribose-5-phosphate isomerase deficiency Transaldolase deficiency Non-alcoholic fatty liver disease Sedoheptulokinase deficiency Teses de mestrado - 2013
Ano:	2013
País:	Portugal
Tipo de documento:	dissertação de mestrado
Tipo de acesso:	acesso aberto
Instituição associada:	Universidade de Lisboa
Idioma:	inglês
Origem:	Repositório da Universidade de Lisboa