Kim Biol 12 Metabolisme Aa dan asam nukleat

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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?
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
g/kg
g/day
Infants (0-1)
~2.2
6.5-20
Children (1-10) 1.8 - 1.25
20- 38
Teens (11-18)
45-55
1.0 - 0.8
Adults (male)
0.8
56
(female) 0.8
44
Pregnant or lactating - 20 - 30% more
Athletes
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
1.2 -1.7
7
PROTEIN AND AMINO ACID METABOLISM
dietary protein
Nitrogen balance
endogenous proteins
digestion
amino acids
a-ketoacids, NH3
other N compounds
glucose, lipids
energy
urea
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
endogenous proteins
DIGESTION
TRANSLATION
amino acids
a-ketoacids, NH3
other N compounds
glucose, lipids
energy
urea
Nitrogen excretion
Dietary protein is
first hydrolyzed to
amino acids, then
rebuilt into
endogenous
protein by
translation.
9
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
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
PROTEIN
TURNOVER
amino acids
a-ketoacids, NH3
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 : 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
Protein Diet
Protein Tubuh
Pool Asam
Amino
Sintesis
Protein:
Asam amino
nonesensial
Protein baru
(struktural,
enzim,
hormon)
NH3
Asam Keto
Senyawa
nitrogen lain:
Heme, Purin,
Pirimidin, dan
Kreatin
Siklus
Krebs
Siklus
Urea
Urea
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
Rangka karbon
Amino
Asam amino
Glukosa
Siklus
Urea
UREA
Keton
AsetilKoA
CO2
Katabolisme Asam Amino
Transaminasi:
transfer gugus
amino ke asam αketoglutarat
menghasilkan asam
glutamat
Deaminasi Oksidatif:
 Pemecahan Glutamat menjadi amonia
dan regenerasi α-ketoglutarat
 Membutuhkan enzim glutamat
dehidrogenase
 α-ketoglutarat digunakan kembali dalam
reaksi transaminasi
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 H2O)→ urea dan
ornitin
4
5
3
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, SuksinilCoA, Fumarat, dan oxaloasetat
Alanin, Sistein,
Glisin, Treonin,
Triptofan, Serin
Glukosa
Asparagin, Aspartat
Isoleusin,
Leusin, Lisin,
Treonin
Asetoasetat
Leusin, Lisin,
Fenilalanin, Triptofan,
Tirosin
Aspartat,
fenilalanin,
Tirosin
Isoleusin,
Metionin, Valin
Arginin, Glutamat,
Glutamin, Histidin,
Prolin
AA esensial
Degradasi menjadi
Arginin
Fenilalanin
α-ketoglutarat
Fumarat, asetoasetil-KoA
Histidin
Isoleusin
Keto Gluko
√
√
√
α-ketoglutarat
Suksinil-KoA, asetil-KoA
√
√
√
Leusin
Asetil-KoA, asetoasetil-KoA
√
Lisin
Asetoasetil-KoA
√
Metionin
Treonin
Suksinil-KoA
Suksinil-KoA, piruvat
Triptofan
Piruvat, asetil-KoA, asetoasetilKoA
Suksinil-KoA
Valin
√
√
√
√
√
AA nonesensial
Alanin
Asparagin
Degradasi menjadi
Keto Gluko
Piruvat
Oksaloasetat
√
√
Aspartat
Glisin
Oksaloasetat, fumarat
Piruvat
√
√
Glutamat
α-ketoglutarat
√
Glutamin
α-ketoglutarat
√
Prolin
Serin
α-ketoglutarat
Piruvat
√
√
Sistein
Tirosin
Piruvat
Asetoasetil-KoA, fumarat
√
√
√
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
O2
Fenilalanin
hidroksilase
H2O
Tirosin
PKU (PhenylKetonUria) : Lack of
Phenylalanine hidroxylase
*Asam amino esensial
Asam amino yang
berasal dari 3Fosfogliserat:
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 cofactors 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)
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 yang berfungsi sebagai prekursor
asam nukleat 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 oleh
nukleotidase dan nukleosida fosfatase
 Nukleosida diserap langsung
 Degradasi lanjutan
Nukleosida + H2O  basa + ribosa (nukleosidase)
Nukleosida + Pi  basa + r-1-fosfate (n. fosforilase)
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 sederhana
o 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 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
Sintesis AMP dan GMP
1. Adenilosuksinat sintase
2. Adenilosuksinase
3. IMP dehidrogenase
4. Transamidinase
1
IMP
3
AMPs
XMP
2
4
AMP
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

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