METABOLISME ASAM AMINO KIMIA BIOLOGIS 2011

Transkripsi

1 METABOLISME ASAM AMINO KIMIA BIOLOGIS 2011

2 Inadequate dietary protein is still a major world problem Two-year old child with kwashiorkor, before and two weeks after start of treatment with good protein. Which is before and which is after? KWASHIORKOR - protein deficiency but adequate calories. Described in 1930s as sickness of older child when new baby is born, in language of Ga tribe of gold coast (now Ghana). Characteristic edema. 2

3 Protein malnutrition, continued FAMINE EDEMA Cause: inadequate synthesis of plasma proteins, especially albumin, so that osmotic pressure is not maintained and fluid escapes into tissues. Body water in extracellular space is increased relative to body weight. Extracellular water: Normal ~23.5% Kwashiokor ~30% 3

4 Protein malnutrition, continued Protein-Energy Malnutrition, Aka Marasmus, Protein-Calorie Deficiency, starvation. Other nutrients (vitamins and minerals) are also likely to be deficient. Starvation is usually the result of war, civil strife, drought, locusts. It especially affects infants and children; growth is slowed, infections and other diseases are common. NY Times, 4/17/00 Ethiopian child 4

5 Protein malnutrition, continued Such extreme forms of malnutrition are rare in US, but protein deficiency can occur among: Pregnant and lactating women, unless they increase their protein intake. Individuals with eating disorders (bulimia, anorexia). Elderly and chronically ill individuals who have lost interest in eating. Chronic alcoholics and substance abusers. Hospital patients with major protein needs and limited capacity for intake (e.g, post-surgery, severe burn victims). Patients with genetic disorders in amino acid absorption or metabolism. 5

6 Dietary protein is the source of essential amino acids Dietary proteins provide the amino acids that humans cannot synthesize - the essential amino acids. The non-essential amino acids can be synthesized endogenously from intermediates of glycolysis or the TCA cycle. Essential Arginine (for children only) Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Threonine Tryptophan Valine Non-essential Alanine Asparagine Aspartate Cysteine Glutamate Glutamine Glycine Proline Serine Tyrosine Mnemonic for essential amino acids: PVT TIM HALL 6

7 How much protein do we need? In contrast to fat and glucose, there is no significant storage pool for amino acids; we must consume protein daily. Requirement for protein depends on age, sex, activity. Proteins differ in content of essential amino acids as well as digestibility. Diets that rely on a single source of protein may be out of balance with our nutritional needs. ALLOWANCE FOR PROTEIN AGE g/kg g/day Infants (0-1) ~ Children (1-10) Teens (11-18) Adults (male) (female) Pregnant or lactating % more REQUIREMENT OF PROTEIN FROM DIFFERENT SOURCES (g/day for 70 kg human) Meat/fish/eggs/milk ~ Non-vegetarian ~ mixed diet Mixed vegetables ~ Single vegetable* up to 75 * Except for soybeans Athletes

8 PROTEIN AND AMINO ACID METABOLISM digestion dietary protein amino acids other N compounds endogenous proteins a-ketoacids, NH 3 glucose, lipids energy urea Nitrogen balance In N balance excretion = intake (healthy adult) Positive N balance excretion < intake (growth, pregnancy, tissue repair) Negative N balance excretion > intake (malnutrition, starvation illness, surgery, burns) Nitrogen excretion 8

9 PROTEIN AND AMINO ACID METABOLISM dietary protein DIGESTION amino acids other N compounds endogenous proteins TRANSLATION a-ketoacids, NH 3 glucose, lipids energy urea Dietary protein is first hydrolyzed to amino acids, then rebuilt into endogenous protein by translation. Nitrogen excretion 9

10 Digestion Mouth: chewing, degradation of starch by amylase make proteins more accessible. Stomach: acid ph denatures proteins; activates pepsinogen to cleave itself to pepsin, which initiates proteolysis. Pancreas (exocrine): secretion of trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidase (inactive proenzymes) Duodenum: peptides from pepsin action stimulate release of cholecystekinin (pancreozymin). Cholecystekinin stimulates release of pancreatic proenzymes and of enteropeptidase, a protease secreted by cells of the duodenum. 10

11 Digestion Duodenum: enteropeptidase activates trypsinogen to trypsin. Trypsin activates the other proteases, each of which has different specificity. Dietary proteins converted to peptides and free amino acids. Small intestine: larger peptides are degraded on the surface of intestinal epithelial cells, which absorb amino acids and small (di- and tri-) peptides. Cytoplasmic peptidases complete conversion of peptides to amino acids, which can enter the circulation. 11

12 Protein and amino acid metabolism dietary protein endogenous proteins amino acids PROTEIN TURNOVER other N compounds a-ketoacids, NH 3 glucose, lipids energy urea Nitrogen excretion 12

13 Siklus Nitrogen

14 Katabolisme Protein Sumber : diet, degradasi protein dalam tubuh Protein dicerna terlebih dahulu sebelum absorbsi Proses cerna usus halus Pencerna : mulut, lambung, pankreas, dan : asam lambung dan berbagai enzim protease Hasil akhir : asam amino bebas Transport : berbagai cara; memerlukan energi atau tidak memerlukan energi

15 Pencernaan Protein

16 Protein Diet Protein Tubuh Pool Asam Amino NH3 Siklus Urea Urea Sintesis Protein: Asam amino nonesensial Protein baru (struktural, enzim, hormon) Senyawa nitrogen lain: Heme, Purin, Pirimidin, dan Kreatin Asam Keto Siklus Krebs CO2 + H2O + ATP

17 Metabolisme Asam Amino Lokasi: intraselular Tahapan: Pelepasan gugus α-amino (transaminasi & deaminasi oksidatif) Gugus amino digunakan untuk biosintesis asam amino, nukleotida, dll; atau disekresikan dalam bentuk urea (siklus urea) Asam α-keto (rangka karbon) dipecah menjadi senyawa lain: glukosa, CO2, asetil Ko-A, atau badan keton

18 Amino Rangka karbon Asam amino Siklus Urea Glukosa Keton Asetil- KoA CO2 UREA Katabolisme Asam Amino

19 Transaminasi: transfer gugus amino ke asam α- ketoglutarat menghasilkan asam glutamat

20 Deaminasi Oksidatif: Pemecahan Glutamat menjadi amonia dan regenerasi α-ketoglutarat Membutuhkan enzim glutamat dehidrogenase α-ketoglutarat digunakan kembali dalam reaksi transaminasi

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22 Siklus Urea Amonia hasil dari pemecahan glutamat digunakan untuk sintesis asam amino baru, sintesis nukleotida, atau senyawa amino lain (porfirin, dll) Amonia berlebih diekskresikan dalam bentuk urea (pada primata) melalui siklus urea

23 Reaksi siklus urea 1 : Karbamoil fosfat sintase 1 kondensasi CO2 dengan amonia karbamoil fosfat 2 : Ornitin transkarbamoilase kondensasi ornitin dengan karbamoil fosfat sitrulin 3 : Argininosuksinat sintetase Kondensasi sitrulin dengan aspartat argininosuksinat 4 : Argininosuksinase Pemecahan argininosuksinat fumarat dan arginin 5 : Arginase Pemecahan arginin (dengan bantuan H 2 O) urea dan ornitin

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25 Siklus Urea dan Siklus Krebs berkaitan

26 Katabolisme rangka karbon asam amino Rangka karbon 20 asam amino mengalami metabolisme lanjut yang berbeda Terdiri dari 2 kelompok besar Ketogenik: didegradasi menjadi senyawa antara metabolisme asam lemak; asetil-koa atau asetoasetat Glukogenik: didegradasi menjadi senyawa antara glikolisis atau SAS; piruvat, α-ketoglutarat, Suksinil- CoA, Fumarat, dan oxaloasetat

27 Alanin, Sistein, Glisin, Treonin, Triptofan, Serin Isoleusin, Leusin, Lisin, Treonin Glukosa Asetoasetat Asparagin, Aspartat Leusin, Lisin, Fenilalanin, Triptofan, Tirosin Aspartat, fenilalanin, Tirosin Isoleusin, Metionin, Valin Arginin, Glutamat, Glutamin, Histidin, Prolin

28 AA esensial Degradasi menjadi Keto Gluko Arginin α-ketoglutarat Fenilalanin Fumarat, asetoasetil-koa Histidin α-ketoglutarat Isoleusin Suksinil-KoA, asetil-koa Leusin Asetil-KoA, asetoasetil-koa Lisin Asetoasetil-KoA Metionin Suksinil-KoA Treonin Suksinil-KoA, piruvat Triptofan Piruvat, asetil-koa, asetoasetil- KoA Valin Suksinil-KoA

29 AA nonesensial Degradasi menjadi Keto Gluko Alanin Piruvat Asparagin Oksaloasetat Aspartat Oksaloasetat, fumarat Glisin Piruvat Glutamat α-ketoglutarat Glutamin α-ketoglutarat Prolin α-ketoglutarat Serin Piruvat Sistein Piruvat Tirosin Asetoasetil-KoA, fumarat

30 Biosintesis Asam Amino Semua asam amino disintesis dari senyawa antara, kecuali tirosin disintesis dari asam amino esensial fenilalanin Asam amino esensial: untuk sintesis protein, tidak dapat dibuat sendiri oleh tubuh, terdapat pada makanan Asam amino non esensial : dapat dibuat oleh tubuh Fenilalanin O 2 H 2 O Tirosin Fenilalanin hidroksilase PKU (PhenylKetonUria) : Lack of Phenylalanine hidroxylase

31 *Asam amino esensial

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34 Asam amino yang berasal dari 3- Fosfogliserat: Serin Sistein Glisin

35 Asam amino yang berasal dari aspartat: Lisin Metionin Treonin

36 Asam amino yang berasal dari piruvat: Leusin Isoleusin Valin

37 Asam amino aromatis: Tirosin Fenilalanin Triptofan

38 Chorismate: Prekursor Asam Amino Aromatis - There is a single precursor for all standard aromatic amino acids - Made from PEP! - From the Pentose Phosphate Pathway (an alternative to glycolysis)

39 Sintesis Histidin

40 Biosintesis Heme - In addition to proteins, some amino acids are used to make cofactors and signaling molecules: - Porphyrins, for example, are made from Succinyl CoA and Glycine

41 Biosintesis Porfirin - The fundamental unit of porphyrins is -aminolevulinate (ALA) - Made by the pyroxidal phosphate (PLP) dependent enzyme - aminolevulinate synthase PLP (vitamin B 6 )

42 Biosintesis Porfirin - We then combine 2 ALA into Porphobilinogen Ring close via Schiff Base

43 Biosintesis Porfirin dari PBG - Porphyrins are composed of 4 PBG subunits - The difference between Uroporphyrinogen I and III

44 METABOLISME NUKLEOTIDA

45 Metabolisme Nukleotida (nukleosida trifosfat) Nukleotida: Senyawa ester fosfat dari suatu gula pentosa dengan basa nitrogen yang terikat pada atom C1 dari pentosa Basa : Purin (Adenin, Guanin) ; Pirimidin (Urasil, Timin, Sitosin) Gula : Ribosa (RNA), Deoksi ribosa (DNA) Unit monomer yang berfungsi sebagai prekursor asam nukleat dan fungsi biokimia lainnya contoh : AMP, GMP, UMP, TMP, CMP

46 Katabolisme Nukleotida Asam nukleat (DNA dan RNA) dari diet didegradasi menjadi nukleotida oleh nuklease pankreas dan fosfodiesterase usus halus Nukleotida didegradasi menjadi nukleosida oleh nukleotidase dan nukleosida fosfatase Nukleosida diserap langsung Degradasi lanjutan Nukleosida + H 2 O basa + ribosa (nukleosidase) Nukleosida + P i basa + r-1-fosfate (n. fosforilase)

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48 Katabolisme Purin (Adenin dan Guanin): 90% digunakan kembali (salvage) (pada mamalia) 10% didegradasi menjadi asam urat Basa adenin inosin hipoksantin; adenosin deaminase, nukleosidase

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50 Asam urat pada beberapa jenis hewan didegradasi lebih lanjut Berbeda antar beberapa golongan hewan Asam urat primata, burung, reptil, serangga Alantoin mamalia lain Asam alantoat ikan Urea ikan bertulang rawan dan amfibi Amonia invertebrata laut

51 Katabolisme Pirimidin (Sitosin, Timin, Urasil): Reaksi : defosforilasilasi, deaminasi, dan pemutusan ikatan glikosida. Urasil dan timin direduksi di hati Produk akhir: ß-alanina (dari sitosin dan urasil) ß-aminoisobutirat (dari timin)

52 Biosintesis Nukleotida Biosintesis purin (Adenin dan Guanin) o Jalur de novo dari prekursor sederhana o Jalur salvage dari hasil degradasinya Biosintesis Pirimidin (Sitosin, Urasil, dan Timin)

53 Biosintesis Purin jalur de novo Diawali dengan sintesis IMP (Inosin MonoPhosphate) Terbuat dari 6 prekursor sederhana (CO2; Glisin; 2 Format; Glutamin; dan Aspartat) Sintesis IMP terdiri dari 11 tahapan reaksi

54 11 tahapan Reaksi Sintesis IMP 1. Aktivasi ribosa-5-fosfat 2. Penambahan glutamin atom N9 3. Penambahan glisin C4, C5, dan N7 4. Penambahan format C8 5. Penambahan glutamin N3 6. Pembentukan cincin imidazola 7. Penambahan bikarbonat C6 8. Penambahan aspartat N1 9. Eliminasi fumarat 10. Penambahan format C2 11. Siklisasi IMP

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56 Sintesis AMP dan GMP 1. Adenilosuksinat sintase 2. Adenilosuksinase 3. IMP dehidrogenase 4. Transamidinase IMP 1 AMPs 2 AMP 3 4 XMP GMP

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58 Regulasi sintesis Purin

59 Biosintesis Purin jalur salvage Penggunaan ulang hasil degradasi nukleotida menjadi nukleotida Memerlukan energi yang lebih rendah daripada sintesis de novo Memerlukan 2 enzim penting HGPRT (hipoksantin-guanin fosforibosil transferase) APRT (Adenin fosforibosil transferase)

60 Jalur salvage Adenin

61 Jalur salvage Guanin

62 Biosintesis Pirimidin Diawali dengan sintesis UMP (Uridin MonoPhosphate) Terbuat dari 3 prekursor sederhana (HCO3-; Aspartat; dan glutamat) Sintesis UMP terdiri dari 6 tahapan reaksi

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64 Sintesis UTP Sintesis CTP

65 E. coli Manusia dan hewan