Metabolisme asam amino Kimia Biologis 2011

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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? Discuss edema 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.

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%

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

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.

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

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. REQUIREMENT OF PROTEIN FROM DIFFERENT SOURCES ( g/day for 70 kg human) Meat/fish/eggs/milk ~ 20-25 Non-vegetarian ~ 25-30 mixed diet Mixed vegetables ~ 30-35 Single vegetable* up to 75 * Except for soybeans

8 PROTEIN AND AMINO ACID METABOLISM
Nitrogen excretion dietary protein amino acids endogenous proteins a-ketoacids, NH3 glucose, lipids energy other N compounds 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) digestion

9 PROTEIN AND AMINO ACID METABOLISM
Nitrogen excretion dietary protein amino acids endogenous proteins a-ketoacids, NH3 glucose, lipids energy other N compounds urea DIGESTION TRANSLATION Dietary protein is first hydrolyzed to amino acids, then rebuilt into endogenous protein by translation.

10 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. Duodenum: peptides from pepsin action stimulate release of cholecystekinin (pancreozymin). Cholecystekinin stimulates release of pancreatic pro-enzymes and of enteropeptidase, a protease secreted by cells of the duodenum. Digestion Pancreas (exocrine): secretion of trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidase (inactive proenzymes)

11 Duodenum: enteropeptidase activates trypsinogen to trypsin
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. Digestion 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.

12 Protein and amino acid metabolism
Nitrogen excretion dietary protein amino acids endogenous proteins a-ketoacids, NH3 glucose, lipids energy other N compounds urea PROTEIN TURNOVER

13 Siklus Nitrogen

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

15 Pencernaan Protein

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

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 Katabolisme Asam Amino
Siklus Urea Glukosa Keton Asetil-KoA CO2 UREA Amino Rangka karbon Asam amino 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 H2O)→ urea dan ornitin

24 4 5 3 2 1

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

28 AA esensial Degradasi menjadi Keto Gluko Arginin α-ketoglutarat √ Fenilalanin Fumarat, asetoasetil-KoA Histidin 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

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

30 Biosintesis Asam Amino
H2O Fenilalanin hidroksilase Fenilalanin Tirosin 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 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 Aspartokinase (we don’t have this)

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 co-factors 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 B6)

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 + H2O  basa + ribosa (nukleosidase) Nukleosida + Pi  basa + r-1-fosfate (n. fosforilase)

47 Purin Pirimidin

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) Jalur de novo → dari prekursor sederhana 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
Aktivasi ribosa-5-fosfat Penambahan glutamin → atom N9 Penambahan glisin → C4, C5, dan N7 Penambahan format → C8 Penambahan glutamin → N3 Pembentukan cincin imidazola Penambahan bikarbonat → C6 Penambahan aspartat → N1 Eliminasi fumarat Penambahan format → C2 Siklisasi IMP

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

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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 Manusia dan hewan E. coli