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?

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

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

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

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

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

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 Infants (0-1) Children (1-10) g/kg ~2.2 1.8 - 1.25

g/day 6.5-20 20- 38 Teens (11-18) 1.0 - 0.8

45-55 Adults (male) (female) 0.8

0.8

56 44 Pregnant or lactating - 20 - 30% more Athletes 1.2 -1.7

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

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PROTEIN AND AMINO ACID METABOLISM

dietary protein

Nitrogen balance

digestion amino acids other N compounds endogenous proteins a-ketoacids, NH glucose, lipids energy urea 3

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

PROTEIN AND AMINO ACID METABOLISM

dietary protein

DIGESTION

amino acids other N compounds endogenous proteins

TRANSLATION

a-ketoacids, NH glucose, lipids energy urea 3

Dietary protein is first hydrolyzed to amino acids, then rebuilt into endogenous protein by translation.

Nitrogen excretion 9

Digestion

•

Mouth

: accessible.

chewing, degradation of starch by amylase make proteins more •

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 pro enzymes and of enteropeptidase, a protease secreted by cells of the duodenum.

10

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

Protein and amino acid metabolism

dietary protein endogenous proteins amino acids

PROTEIN TURNOVER

a-ketoacids, NH 3 other N compounds glucose, lipids energy urea Nitrogen excretion 12

Siklus Nitrogen

Katabolisme Protein

  

Sumber

: diet, degradasi protein dalam tubuh Protein dicerna terlebih dahulu sebelum absorbsi  Proses cerna usus halus : mulut, lambung, pankreas, dan  Pencerna enzim protease : asam lambung dan berbagai  Hasil akhir : asam amino bebas

Transport

: berbagai cara; memerlukan energi atau tidak memerlukan energi

Pencernaan Protein

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

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

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

Katabolisme 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 dehidrogenase glutamat



α-ketoglutarat digunakan kembali reaksi transaminasi dalam

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

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) → ornitin

urea

dan

3 4 5 2 1

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

Glukosa

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

AA esensial

Arginin Fenilalanin Histidin Isoleusin

Leusin Lisin

Metionin Treonin Triptofan Valin

Degradasi menjadi

α-ketoglutarat Fumarat, asetoasetil-KoA α-ketoglutarat Suksinil-KoA, asetil-KoA Asetil-KoA, asetoasetil-KoA Asetoasetil-KoA Suksinil-KoA Suksinil-KoA, piruvat Piruvat, asetil-KoA, asetoasetil KoA Suksinil-KoA

Keto Gluko

√ √ √ √ √ √ √ √ √ √ √ √ √

AA non esensial

Alanin Asparagin Aspartat Glisin Glutamat Glutamin Prolin Serin Sistein Tirosin

Degradasi menjadi

Piruvat Oksaloasetat Oksaloasetat, fumarat Piruvat α-ketoglutarat α-ketoglutarat α-ketoglutarat Piruvat Piruvat Asetoasetil-KoA , fumarat

Keto Gluko

√ √ √ √ √ √ √ √ √ √ √

Biosintesis Asam Amino

Fenilalanin

• • • 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

: O 2 H 2 O Tirosin Fenilalanin hidroksilase

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

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 B 6 )

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

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

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 asam nukleat yang berfungsi sebagai prekursor dan fungsi biokimia lainnya contoh : 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 nukleotidase dan nukleosida fosfatase oleh  Nukleosida diserap langsung  Degradasi lanjutan Nukleosida + H 2 O  basa + ribosa (nukleosidase) Nukleosida + P i  basa + r-1-fosfate (n. fosforilase)

Katabolisme Purin (Adenin dan Guanin):  90% digunakan kembali (salvage) mamalia) (pada   10% didegradasi menjadi asam urat Basa

adenin

→ inosin → deaminase, nukleosidase

hipoksantin

; adenosin

 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 Produk akhir :  ß-alanina direduksi (dari sitosin dan urasil)  ß-aminoisobutirat (dari timin) di hati

Biosintesis Nukleotida

  Biosintesis purin (Adenin dan Guanin) o o Jalur

de novo → dari prekursor sederhana

Jalur

salvage → dari hasil degradasinya

Biosintesis Pirimidin (Sitosin, Urasil, dan Timin)

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

11 tahapan Reaksi Sintesis IMP

1.

2.

3.

4.

5.

Aktivasi ribosa-5-fosfat Penambahan glutamin → atom N9 Penambahan glisin → C4, C5, dan N7 Penambahan format → C8 Penambahan glutamin → N3 6.

7.

8.

Pembentukan cincin imidazola Penambahan bikarbonat → C6 Penambahan aspartat → N1 9.

Eliminasi fumarat 10.

Penambahan format → C2 11.

Siklisasi IMP

Sintesis AMP dan GMP

1.

2.

Adenilosuksinat sintase Adenilosuksinase 3.

4.

IMP dehidrogenase Transamidinase

AMPs IMP 1 2 AMP 3 XMP 4 GMP

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. coli Manusia dan hewan