Gluconeogenesi e via dei Pentosi fosfato

Gluconeogenesi Sintesi di glucoso da metaboliti intermedi Nell’uomo si consumano 160 g di glucoso/giorno Il cervello da solo ne consuma il 75% Il glicogeno contiene circa 180-200 g di glucoso

Piruvico, lattato, glicerolo, aminoacidi, intermedi del ciclo di Krebs possono essere utilizzati nella glucogenesi Gli acidi grassi non possono essere utilizzati nella glucogenesi perché producono solo acetil-coA che non può essere riconvertito a glucosio

La gluconeogenesi è un processo prevalentemente epatico e renale. Essa condivide alcune tappe (7) con la via glicolitica ma non è il suo inverso. Le reazioni con un DG molto negativo, quindi irreversibili, devono essere bypassate

I° tappa irreversibile: Piruvico PEP Il bypass implica due reazioni: piruvico ossalacetico ossalacetico PEP

PIRUVICO CARBOSSILASI I° reazione PIRUVICO CARBOSSILASI

La carbossilazione del piruvico è un evento MITOCONDRIALE

Il piruvato è convertito in ossalacetato Come coenzima viene utilizzata la Biotina (covalentemente legata all’enzima, interviene in tutte le reazioni di carbossilazione) L’Acetil-CoA è l’attivatore allosterico Questa è la via attraverso cui, se le concentrazioni di ATP o acetil-CoA sono alte, il piruvico intraprende la gluconeogenesi

FOSFOENOLPIRUVICO CARBOSSICHINASI II° reazione FOSFOENOLPIRUVICO CARBOSSICHINASI

Fructose-1,6-bisphosphatase II bypass Fruttoso 1,6 difosfato Fruttoso 6P Fructose-1,6-bisphosphatase Catalizza l’idrolisi del F-1,6-P a F-6P E’ regolato allostericamente da: citrato (attivatore) fruttoso-2,6-bisfosfato (inibitore) AMP (inibitore)

Glucoso-6-Fosfatasi III bypass Glucoso 6-fosfato Glucoso Converte il Glucoso-6-P in Glucoso L’enzima si trova sul reticolo endoplasmatico del fegato e del rene Il Glucoso-6P viene idrolizzato a Glucosio quando passa nel RE.

FIGURE 15-28 Hydrolysis of glucose 6-phosphate by glucose 6-phosphatase of the ER. The catalytic site of glucose 6-phosphatase faces the lumen of the ER. A glucose 6-phosphate (G6P) transporter (T1) carries the substrate from the cytosol to the lumen, and the products glucose and Pi pass to the cytosol on specific transporters (T2 and T3). Glucose leaves the cell via the GLUT2 transporter in the plasma membrane.

Il Ciclo dei Pentosi Fosfato

VIA DEI PENTOSI FOSFATO (Shunt degli esosi monofosfato) Produce NADPH per le biosintesi Produce riboso-5-P E’ costituito da due tappe ossidative seguito da 5 tappe non ossidative Avviene principalmente nel citoplasma degli epatociti e degli adipociti Il NADPH è utilizzato nel citosol per la biosintesi degli acidi grassi 25

Tappe Ossidative Glucoso-6-P Deidrogenasi 1° tappa irreversibile – altamente regolata 6-fosfogluconico Deidrogenasi 2° tappa decarbossilazione ossidativa

FIGURE 14-21 Oxidative reactions of the pentose phosphate pathway FIGURE 14-21 Oxidative reactions of the pentose phosphate pathway. The end products are ribose 5-phosphate, CO2, and NADPH.

FIGURE 14-21 (part 1) Oxidative reactions of the pentose phosphate pathway. The end products are ribose 5-phosphate, CO2, and NADPH.

FIGURE 14-21 (part 2) Oxidative reactions of the pentose phosphate pathway. The end products are ribose 5-phosphate, CO2, and NADPH.

FIGURE 14-21 (part 3) Oxidative reactions of the pentose phosphate pathway. The end products are ribose 5-phosphate, CO2, and NADPH.

LE TAPPE NON OSSIDATIVE Fosfopentoso isomerasi Converte i chetosi in aldosi Fosfopentoso epimerasi epimerizzazione al C-3 Transchetolasi (TPP-dipendente) Trasferimento di unità a due atomi di C Transaldolasi (Schiff base) Trasferimemento di unità a tre atomi di C 27

FIGURE 14-21 (part 4) Oxidative reactions of the pentose phosphate pathway. The end products are ribose 5-phosphate, CO2, and NADPH.

FIGURE 14-22 Nonoxidative reactions of the pentose phosphate pathway FIGURE 14-22 Nonoxidative reactions of the pentose phosphate pathway. (a) These reactions convert pentose phosphates to hexose phosphates, allowing the oxidative reactions (see Figure 14-21) to continue. Transketolase and transaldolase are specific to this pathway; the other enzymes also serve in the glycolytic or gluconeogenic pathways. (b) A schematic diagram showing the pathway from six pentoses (5C) to five hexoses (6C). Note that this involves two sets of the interconversions shown in (a). Every reaction shown here is reversible; unidirectional arrows are used only to make clear the direction of the reactions during continuous oxidation of glucose 6-phosphate. In the light-independent reactions of photosynthesis, the direction of these reactions is reversed (see Figure 20-10).

FIGURE 14-22a Nonoxidative reactions of the pentose phosphate pathway FIGURE 14-22a Nonoxidative reactions of the pentose phosphate pathway. (a) These reactions convert pentose phosphates to hexose phosphates, allowing the oxidative reactions (see Figure 14-21) to continue. Transketolase and transaldolase are specific to this pathway; the other enzymes also serve in the glycolytic or gluconeogenic pathways.

FIGURE 14-22b Nonoxidative reactions of the pentose phosphate pathway FIGURE 14-22b Nonoxidative reactions of the pentose phosphate pathway. (b) A schematic diagram showing the pathway from six pentoses (5C) to five hexoses (6C). Note that this involves two sets of the interconversions shown in (a). Every reaction shown here is reversible; unidirectional arrows are used only to make clear the direction of the reactions during continuous oxidation of glucose 6-phosphate. In the light-independent reactions of photosynthesis, the direction of these reactions is reversed (see Figure 20-10).

Lo shunt può dare prodotti differenti in rapporto alle necessità cellulari 1) riboso-5-P e NADPH in egual misura 2) più riboso-5-P che NADPH 3) Più NADPH che riboso-5-P 4) NADPH e ATP, ma non riboso-5-P

FIGURE 14-20 General scheme of the pentose phosphate pathway FIGURE 14-20 General scheme of the pentose phosphate pathway. NADPH formed in the oxidative phase is used to reduce glutathione, GSSG (see Box 14-4) and to support reductive biosynthesis. The other product of the oxidative phase is ribose 5-phosphate, which serves as a precursor for nucleotides, coenzymes, and nucleic acids. In cells that are not using ribose 5-phosphate for biosynthesis, the nonoxidative phase recycles six molecules of the pentose into five molecules of the hexose glucose 6-phosphate, allowing continued production of NADPH and converting glucose 6-phosphate (in six cycles) to CO2.

BOX 14-4 FIGURE 1 Role of NADPH and glutathione in protecting cells against highly reactive oxygen derivatives. Reduced glutathione (GSH) protects the cell by destroying hydrogen peroxide and hydroxyl free radicals. Regeneration of GSH from its oxidized form (GSSG) requires the NADPH produced in the glucose 6-phosphate dehydrogenase reaction.

FIGURE 14-20 General scheme of the pentose phosphate pathway FIGURE 14-20 General scheme of the pentose phosphate pathway. NADPH formed in the oxidative phase is used to reduce glutathione, GSSG (see Box 14-4) and to support reductive biosynthesis. The other product of the oxidative phase is ribose 5-phosphate, which serves as a precursor for nucleotides, coenzymes, and nucleic acids. In cells that are not using ribose 5-phosphate for biosynthesis, the nonoxidative phase recycles six molecules of the pentose into five molecules of the hexose glucose 6-phosphate, allowing continued production of NADPH and converting glucose 6-phosphate (in six cycles) to CO2.

FIGURE 14-23a The first reaction catalyzed by transketolase FIGURE 14-23a The first reaction catalyzed by transketolase. (a) The general reaction catalyzed by transketolase is the transfer of a two-carbon group, carried temporarily on enzyme-bound TPP, from a ketose donor to an aldose acceptor.

FIGURE 14-23b The first reaction catalyzed by transketolase FIGURE 14-23b The first reaction catalyzed by transketolase. (b) Conversion of two pentose phosphates to a triose phosphate and a seven-carbon sugar phosphate, sedoheptulose 7-phosphate.

FIGURE 14-24 The reaction catalyzed by transaldolase.

FIGURE 14-25 The second reaction catalyzed by transketolase.

FIGURE 14-27 Role of NADPH in regulating the partitioning of glucose 6-phosphate between glycolysis and the pentose phosphate pathway. When NADPH is forming faster than it is being used for biosynthesis and glutathione reduction (see Figure 14-20), [NADPH] rises and inhibits the first enzyme in the pentose phosphate pathway. As a result, more glucose 6-phosphate is available for glycolysis.