Spec. Pepsina: aa aromatici, acidi e Leu

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2 Spec. Pepsina: aa aromatici, acidi e Leu
(Cellule adelomorfe) Spec. Pepsina: aa aromatici, acidi e Leu FIGURE 18-3 Part of the human digestive (gastrointestinal) tract. (a) The parietal cells and chief cells of the gastric glands secrete their products in response to the hormone gastrin. Pepsin begins the process of protein degradation in the stomach. (b) The cytoplasm of exocrine cells is completely filled with rough endoplasmic reticulum, the site of synthesis of the zymogens of many digestive enzymes. The zymogens are concentrated in membrane-enclosed transport particles called zymogen granules. When an exocrine cell is stimulated, its plasma membrane fuses with the zymogen granule membrane and zymogens are released into the lumen of the collecting duct by exocytosis. The collecting ducts ultimately lead to the pancreatic duct and thence to the small intestine. (c) Amino acids are absorbed through the epithelial cell layer (intestinal mucosa) of the villi and enter the capillaries. Recall that the products of lipid hydrolysis in the small intestine enter the lymphatic system after their absorption by the intestinal mucosa (see Figure 17-1).

3 Ormoni attivi nella digestione
Gastrina: ormone peptidico prodotto dalle cellule G presenti nella mucosa pilorica dello stomaco e nella parte prossimale del tenue, la cui funzione principale è regolare la secrezione di HCl e pepsinogeno. Gli stimoli alla sua produzione possono essere di natura: meccanica (cioè la distensione delle pareti dello stomaco) chimica (ad opera di peptidi, amminoacidi, alcool o un ambiente intragastrico troppo basico). Secretina: ormone peptidico rilasciato nel sangue dalle cellule S delle cripte del Lieberkühn del duodeno quando il contenuto dello stomaco passa nell’intestino; stimola il pancreas a secernere HCO3- nell’intestino. Colecistochinina: ormone peptidico rilasciato nel sangue dalle cellule I dell’intestino quando arrivano amminoacidi e grassi nel duodeno; stimola la secrezione degli enzimi pancreatici e della bile. Sopprime il senso di fame.

4 Attivazione proteolitica degli zimogeni
Proteasi secreta da cellule delle cripte del Lieberkühn del duodeno in risposta al passaggio di cibo dallo stomaco all’intestino. Inibitore pancreatico della tripsina

5 Assorbimento intestinale degli amminoacidi
Trasportatori situati nell’orletto a spazzola degli enterociti – funzionano in simporto con Na+ Identificati 4 sistemi di trasporto: Trasportatore degli amminoacidi neutri Trasportatore degli amminoacidi basici (anche Cys) Trasportatore degli amminoacidi bicarbossilici (acidi) Trasportatore per Gly e Pro

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7 Amminoacidi essenziali per l’uomo
Fenilalanina Isoleucina Istidina Leucina Lisina Metionina Treonina Triptofano Valina (Arginina)

8 Eliminazione dell’azoto

9 Destino dell’azoto FIGURE 18-2b Amino group catabolism. (b) Excretory forms of nitrogen. Excess NH4+ is excreted as ammonia (microbes, bony fishes), urea (most terrestrial vertebrates), or uric acid (birds and terrestrial reptiles). Notice that the carbon atoms of urea and uric acid are highly oxidized; the organism discards carbon only after extracting most of its available energy of oxidation.

10 Reazione di transamminazione

11 FIGURE 18-4 Enzyme-catalyzed transaminations
FIGURE 18-4 Enzyme-catalyzed transaminations. In many aminotransferase reactions, α-ketoglutarate is the amino group acceptor. All aminotransferases have pyridoxal phosphate (PLP) as cofactor. Although the reaction is shown here in the direction of transfer of the amino group to α-ketoglutarate, it is readily reversible

12 Piridossale Piridossamina

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16 A

17 A Aspar

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19 Vitamina B6 VITAMERI: La piridossina, il piridossale e la piridossamina (e i corrispondenti esteri 5' fosfati - il più noto è il piridossal-fosfato) sono le forme con cui si presenta la vitamina B6. Il piridossalfosfato è la forma attiva della vitamina B6 e un cofattore di enzimi transferasi come le transaminasi. FONTI: La vitamina B6 è presente nei cibi sia di origine animale che vegetale. Generalmente nei primi vi è una maggior quantità di piridossamina e piridossale fosforilati mentre nei secondi prevale la piridossina. RDA: 1-2 mg/die CARENZA: La carenza di vitamina B6 è rara. Studi su volontari che hanno assunto un antagonista della vitamina hanno registrato comparsa di depressione con nausea, vomito, dermatite seborroica, lesioni delle mucose, glossite e neuropatie periferiche.

20 Aspartato amminotransferasi (AST)

21 Aspartato amminotransferasi (AST)
FIGURE 18-5c Pyridoxal phosphate, the prosthetic group of aminotransferases. (c) PLP (red) bound to one of the two active sites of the dimeric enzyme aspartate aminotransferase, a typical aminotransferase

22 Glu deidrogenasi (presente nei mitocondri, formato da 6 subunità)
FIGURE 18-7 Reaction catalyzed by glutamate dehydrogenase. The glutamate dehydrogenase of mammalian liver has the unusual capacity to use either NAD+ or NADP+ as cofactor. The glutamate dehydrogenases of plants and microorganisms are generally specific for one or the other. The mammalian enzyme is allosterically regulated by GTP and ADP.

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24 Ser/Thr deidratasi

25 Ser/Thr deidratasi a-chetobutirrato decarbossilato a propionil-CoA

26 Catabolismo del gruppo amminico (fegato)
FIGURE 18-2 Amino group catabolism. (a) Overview of catabolism of amino groups (shaded) in vertebrate liver.

27 Trasporto di ammoniaca come glutammina
FIGURE 18-8 Ammonia transport in the form of glutamine. Excess ammonia in tissues is added to glutamate to form glutamine, a process catalyzed by glutamine synthetase. After transport in the bloodstream, the glutamine enters the liver and NH4+ is liberated in mitochondria by the enzyme glutaminase

28 Ciclo muscolo-epatico alanina glucosio
FIGURE 18-9 Glucose-alanine cycle. Alanine serves as a carrier of ammonia and of the carbon skeleton of pyruvate from skeletal muscle to liver. The ammonia is excreted and the pyruvate is used to produce glucose, which is returned to the muscle.

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30 Carbamil fosfato sintetasi I

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32 + H2O

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34 Urea ematica 5 mM Nel caso di grave insufficienza epatica 250 mM

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36 Nel citosol

37 Urea + 2 ADP + 2 Pi + AMP + PPi + fumarato
Stechiometria del ciclo dell’urea CO2 + NH ATP + Asp + 2H2O  Urea + 2 ADP + 2 Pi + AMP + PPi + fumarato

38 FIGURE (part 1) Urea cycle and reactions that feed amino groups into the cycle. The enzymes catalyzing these reactions (named in the text) are distributed between the mitochondrial matrix and the cytosol. One amino group enters the urea cycle as carbamoyl phosphate, formed in the matrix; the other enters as aspartate, formed in the matrix by transamination of oxaloacetate and glutamate, catalyzed by aspartate aminotransferase. The urea cycle consists of four steps. 1 Formation of citrulline from ornithine and carbamoyl phosphate (entry of the first amino group); the citrulline passes into the cytosol. 2 Formation of argininosuccinate through a citrullyl-AMP intermediate (entry of the second amino group). 3 Formation of arginine from argininosuccinate; this reaction releases fumarate, which enters the citric acid cycle. 4 Formation of urea; this reaction also regenerates ornithine. The pathways by which NH4+ arrives in the mitochondrial matrix of hepatocytes were discussed in Section 18.1.

39 FIGURE (part 2) Urea cycle and reactions that feed amino groups into the cycle. The enzymes catalyzing these reactions (named in the text) are distributed between the mitochondrial matrix and the cytosol. One amino group enters the urea cycle as carbamoyl phosphate, formed in the matrix; the other enters as aspartate, formed in the matrix by transamination of oxaloacetate and glutamate, catalyzed by aspartate aminotransferase. The urea cycle consists of four steps. 1 Formation of citrulline from ornithine and carbamoyl phosphate (entry of the first amino group); the citrulline passes into the cytosol. 2 Formation of argininosuccinate through a citrullyl-AMP intermediate (entry of the second amino group). 3 Formation of arginine from argininosuccinate; this reaction releases fumarate, which enters the citric acid cycle. 4 Formation of urea; this reaction also regenerates ornithine. The pathways by which NH4+ arrives in the mitochondrial matrix of hepatocytes were discussed in Section 18.1.

40 FIGURE 18-12 Links between the urea cycle and citric acid cycle
FIGURE Links between the urea cycle and citric acid cycle. The interconnected cycles have been called the "Krebs bicycle." The pathways linking the citric acid and urea cycles are known as the aspartate-argininosuccinate shunt; these effectively link the fates of the amino groups and the carbon skeletons of amino acids. The interconnections are even more elaborate than the arrows suggest. For example, some citric acid cycle enzymes, such as fumarase and malate dehydrogenase, have both cytosolic and mitochondrial isozymes. Fumarate produced in the cytosol—whether by the urea cycle, purine biosynthesis, or other processes—can be converted to cytosolic malate, which is used in the cytosol or transported into mitochondria (via the malateaspartate shuttle; see Figure 19-29) to enter the citric acid cycle.

41 N-acetilglutammato come regolatore del ciclo dell’urea
Acetil-CoA, Glu e Arg segnalano che energia e intermedi per il ciclo dell’urea sono disponibili FIGURE Synthesis of N-acetylglutamate and its activation of carbamoyl phosphate synthetase I.

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43 FIGURE 18-15 Summary of amino acid catabolism
FIGURE Summary of amino acid catabolism. Amino acids are grouped according to their major degradative end product. Some amino acids are listed more than once because different parts of their carbon skeletons are degraded to different end products. The figure shows the most important catabolic pathways in vertebrates, but there are minor variations among vertebrate species. Threonine, for instance, is degraded via at least two different pathways (see Figure 18-19, 18-27), and the importance of a given pathway can vary with the organism and its metabolic conditions. The glucogenic and ketogenic amino acids are also delineated in the figure, by color shading. Notice that five of the amino acids are both glucogenic and ketogenic. The amino acids degraded to pyruvate are also potentially ketogenic. Only two amino acids, leucine and lysine, are exclusively ketogenic.

44 Amminoacidi che danno piruvato

45 Amminoacidi che danno a-chetoglutarato

46 Amminoacidi che danno ossalacetato
FIGURE Catabolic pathway for asparagine and aspartate. Both amino acids are converted to oxaloacetate.

47 Amminoacidi che danno succinil-CoA

48 Ciclo muscolo-epatico alanina glucosio

49 Berg et al. , BIOCHIMICA 6/E, Zanichelli editore S. p. A
Berg et al., BIOCHIMICA 6/E, Zanichelli editore S.p.A. Copyright © 2007

50 Degradazione di Phe e Tyr
* ** *Phe idrossilasi: Phe + O2 +NADPH + H+  Tyr + NADP+ + H2O Deficit: fenilchetonuria (Phe e Phepyr nelle urine, ritardo mentale) ** Omogentisato ossidasi: Omogentisato + O2  maleilacetato + H+ Deficit: Alcaptonuria (omogentisato nelle urine, all’aria dà un polimero di colore scuro)

51 Trattamento della carenza di
Argininosuccinasi Dieta arricchita in Arg e limitata assunzione di proteine

52 Trattamento della carenza di carbamil fosfato sintetasi e OTC
Dieta povera di proteine integrata con grandi quantità di benzoato e fenilacetato