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

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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