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Metabolisme asam amino Kimia Biologis 2011. 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?. - PowerPoint PPT Presentation
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METABOLISME ASAM AMINO
KIMIA BIOLOGIS 2011
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Inadequate dietary protein is still a major world problem
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.
Two-year old child with kwashiorkor, before and two weeks after start of treatment with good protein.
Which is before and which is after?
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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%
Protein malnutrition, continued
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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.
Protein malnutrition, continued
NY Times, 4/17/00Ethiopian child
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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.
Protein malnutrition, continued
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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.
EssentialArginine (for children only)HistidineIsoleucineLeucineLysineMethioninePhenylalanineThreonineTryptophanValine
Non-essential AlanineAsparagineAspartateCysteineGlutamateGlutamineGlycineProlineSerineTyrosine
Mnemonic for essential amino acids: PVT TIM HALL
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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) ~2.2 6.5-20
Children (1-10) 1.8 - 1.25 20- 38
Teens (11-18) 1.0 - 0.8 45-55
Adults (male) 0.8 56(female) 0.8 44
Pregnant or lactating - 20 - 30% more
Athletes 1.2 -1.7
REQUIREMENT OF PROTEINFROM DIFFERENT SOURCES
(g/day for 70 kg human)
Meat/fish/eggs/milk ~ 20-25Non-vegetarian ~ 25-30
mixed dietMixed vegetables ~ 30-35Single vegetable* up to 75
* Except for soybeans
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PROTEIN AND AMINO ACID METABOLISM
Nitrogen excretion
dietary protein
amino acids
endogenous proteins
a-ketoacids, NH3
glucose, lipidsenergy
other N compounds
urea
Nitrogen balanceIn N balance excretion = intake (healthy adult)Positive N balance excretion < intake (growth, pregnancy, tissue repair)Negative N balanceexcretion > intake (malnutrition, starvation illness, surgery, burns)
digestion
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PROTEIN AND AMINO ACID METABOLISM
Dietary protein is first hydrolyzed to amino acids, then rebuilt into endogenous protein by translation.
Nitrogen excretion
dietary protein
amino acids
endogenous proteins
a-ketoacids, NH3
glucose, lipidsenergy
other N compounds
urea
DIGESTIONTRANSLATION
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• 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)
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• 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.
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Protein and amino acid metabolism
Nitrogen excretion
dietary protein
amino acids
endogenous proteins
a-ketoacids, NH3
glucose, lipidsenergy
other N compounds
urea
PROTEIN TURNOVER
Siklus Nitrogen
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
Pencernaan Protein
Pool Asam Amino
Siklus Urea
Protein Diet Protein Tubuh
Asam Keto
Sintesis Protein:Asam amino nonesensialProtein baru (struktural, enzim, hormon)
Senyawa nitrogen lain: Heme, Purin, Pirimidin, dan Kreatin
CO2 + H2O + ATP
NH3
Urea
Siklus Krebs
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
Katabolisme Asam Amino
Siklus Urea
Glukosa Keton Asetil-
KoACO2
UREA
AminoRangka karbon
Asam amino
Transaminasi: transfer gugus amino ke asam α-ketoglutarat menghasilkan asam glutamat
Deaminasi Oksidatif: Pemecahan Glutamat menjadi
amonia dan regenerasi α-ketoglutarat
Membutuhkan enzim glutamat dehidrogenase
α-ketoglutarat digunakan kembali dalam reaksi transaminasi
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
Siklus Urea
Reaksi siklus urea1 : Karbamoil fosfat sintase 1
kondensasi CO2 dengan amonia → karbamoil fosfat
2 : Ornitin transkarbamoilasekondensasi ornitin dengan karbamoil fosfat → sitrulin
3 : Argininosuksinat sintetaseKondensasi sitrulin dengan aspartat → argininosuksinat
4 : Argininosuksinase Pemecahan argininosuksinat → fumarat dan arginin
5 : ArginasePemecahan arginin (dengan bantuan H2O)→ urea dan ornitin
1
23
4 5
Siklus Urea dan Siklus Krebs berkaitan
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
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
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 √
AA non- esensial
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 √ √
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
CH2CHCO2-
NH3+
CH2CHCO2-
NH3+
HO
O2
H2O
Fenilalanin hidroksilase
Fenilalanin
Tirosin
PKU (PhenylKetonUria) : Lack of Phenylalanine hidroxylase
*Asam amino esensial
Asam amino yang berasal dari 3-Fosfogliserat:Serin
Sistein
Glisin
Asam amino yang berasal dari aspartat:
Lisin
Metionin
Treonin
Aspartokinase
(we don’t have
this)
Asam amino yang berasal dari piruvat:
Leusin
Isoleusin
Valin
Asam amino aromatis:
Tirosin
Fenilalanin
Triptofan
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)
Sintesis Histidin
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
Biosintesis Porfirin
- The fundamental unit of porphyrins is -aminolevulinate (ALA)- Made by the pyroxidal phosphate (PLP) dependent enzyme -aminolevulinate synthase
PLP (vitamin B6)
- We then combine 2 ALA into Porphobilinogen
Ring close via Schiff Base
Biosintesis Porfirin
- Porphyrins are composed of 4 PBG subunits
- The difference between Uroporphyrinogen I and III
Biosintesis Porfirin dariPBG
METABOLISME NUKLEOTIDA
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 lainnyacontoh : AMP, GMP, UMP, TMP, CMP
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)
PurinPirimidin
Katabolisme Purin (Adenin dan Guanin): 90% digunakan kembali (salvage) (pada
mamalia) 10% didegradasi menjadi asam urat Basa adenin → inosin → hipoksantin;
adenosin deaminase, nukleosidase
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
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)
Biosintesis Nukleotida
Biosintesis purin (Adenin dan Guanin)o Jalur de novo → dari prekursor sederhanao Jalur salvage → dari hasil degradasinya
Biosintesis Pirimidin (Sitosin, Urasil, dan Timin)
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
11 tahapan Reaksi Sintesis IMP1. Aktivasi ribosa-5-fosfat2. Penambahan glutamin → atom N93. Penambahan glisin → C4, C5, dan N74. Penambahan format → C85. Penambahan glutamin → N36. Pembentukan cincin imidazola7. Penambahan bikarbonat → C68. Penambahan aspartat → N19. Eliminasi fumarat10.Penambahan format → C211.Siklisasi IMP
Sintesis AMP dan GMP1. Adenilosuksinat sintase2. Adenilosuksinase3. IMP dehidrogenase4. Transamidinase
AMPs
XMP
IMP AMP
GMP
1
3 4
2
Regulasi sintesis Purin
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)
Jalur salvage Adenin
Jalur salvage Guanin
Biosintesis Pirimidin Diawali dengan sintesis UMP (Uridin
MonoPhosphate) Terbuat dari 3 prekursor sederhana
(HCO3-; Aspartat; dan glutamat) Sintesis UMP terdiri dari 6 tahapan reaksi
Sintesis UTP
Sintesis CTP
E. coliManusia dan hewan