متابولیسم چربیها. Text Cholesterol Phospholipid Triglycerides Bile Salts T G Emulsion...

متابولیسم چربیهامتابولیسم چربیها

Cholesterol

Phospholipid

Triglycerides Bile Salts T G Emulsion Lipase

Fatty acids +Monoglycrid+Diglycrid

<10 carbone Absorbed

> 10 C in Intestine Cells with cholesterol &phspholipid &M.G &D.G& Protein Chylomicrones

Cholesterol

Phospholipid

Triglycerides Bile Salts T G Emulsion Lipase

Fatty acids +Monoglycrid+Diglycrid

<10 carbone Absorbed

> 10 C in Intestine Cells with cholesterol &phspholipid &M.G &D.G& Protein Chylomicrones

IntroductionIntroduction

The lipases break the triacylglycerols down to fatty acids and glycerol

The fatty acids are transportred in the blood by serum albumin

The lipases break the triacylglycerols down to fatty acids and glycerol

The fatty acids are transportred in the blood by serum albumin

Breakdown of TriacylglycerolsBreakdown of Triacylglycerols

Transport into Mitochondrial MatrixTransport into Mitochondrial Matrix

Fatty acid oxidationFatty acid oxidationAcyl-CoA Synthetase

Acyl-CoA Synthetase

یک الکترون FADH2درهرمرحله انتقال زنجیر در میشودکه تولید2ATP. میدهد

یک میشودکه NADH2درهرمرحله الکترون تولید انتقال زنجیر در3ATP.مدهید

کربس سیکل در میشودکه تولید آ کوآنزیم استیل یک درهرمرحله12ATP.میدهد

بتااکسیداسیون مرحله هر در . 17ATPپس میشود تولیدچرب اسید بتا 2nاگر واکنشهای باشد آن ساختمان در کربن.n-1اکسیداسیون . داشت خواهیم بنابراین میشود تکرار مرتبه

ودومی کوآداریم استیل دو پایان در میکند 12ATPچون تولیدATP=17(n-1)+12

ابتدا در :2ATPوچون بنابراین . شد مصرفATP=17(n-1)+10ATP=17n – 7

باشد . فرد چرب اسید کربن تعداد کرده 3اگر کم چرب ازاسید کربنپایان ودر نموده عمل باال . 6ATPوطبق میکنیم اضافه آن به

باشد . فرد چرب اسید کربن تعداد کرده 3اگر کم چرب ازاسید کربنمیکنیم . استفاده زیر ATP= 17n-ازرابطه

1

یک الکترون FADH2درهرمرحله انتقال زنجیر در میشودکه تولید2ATP. میدهد

یک میشودکه NADH2درهرمرحله الکترون تولید انتقال زنجیر در3ATP.مدهید






باشد . فرد چرب اسید کربن تعداد کرده 3اگر کم چرب ازاسید کربنمیکنیم . استفاده زیر -ATP= 17nازرابطه

1

ATP YieldATP Yield

)جدید) چربیها سوختن انرژی (جدید)محاسبه چربیها سوختن انرژی محاسبهیک الکترون FADH2درهرمرحله انتقال زنجیر در میشودکه تولید

1/5ATP. میدهدیک میشودکه NADH2درهرمرحله الکترون تولید انتقال زنجیر در

2/5ATP.مدهیدکربس سیکل در میشودکه تولید آ کوآنزیم استیل یک درهرمرحله

10ATP.میدهدبتااکسیداسیون مرحله هر در . 14ATPپس میشود تولید

چرب اسید بتا 2nاگر واکنشهای باشد آن ساختمان در کربن.n-1اکسیداسیون . داشت خواهیم بنابراین میشود تکرار مرتبه




باشد . فرد چرب اسید کربن تعداد کرده 3اگر کم چرب ازاسید کربنمیکنیم . استفاده زیر ATP= 14n-ازرابطه

1

یک الکترون FADH2درهرمرحله انتقال زنجیر در میشودکه تولید1/5ATP. میدهد

یک میشودکه NADH2درهرمرحله الکترون تولید انتقال زنجیر در2/5ATP.مدهید






باشد . فرد چرب اسید کربن تعداد کرده 3اگر کم چرب ازاسید کربنمیکنیم . استفاده زیر -ATP= 14nازرابطه

1

Ketone BodiesKetone Bodies

Use of fatty acids in the citric acid cycle requires carbohydrates for the the production of oxaloacetate.

During starvation or diabetes, OAA is used to make glucose

Fatty acids are then used to make ketone bodies (acetoacetate and D–3–hydroxybutarate)

Use of fatty acids in the citric acid cycle requires carbohydrates for the the production of oxaloacetate.

During starvation or diabetes, OAA is used to make glucose

Fatty acids are then used to make ketone bodies (acetoacetate and D–3–hydroxybutarate)

ستونی ستونی ترکیبات ترکیبات

1- اسید استیک .استو -2 اسید بوتیریک هیدرکسی .بتا

استون3- متابولیسم در اختاللی هرگاه

کوآ استیل شود ایجاد کربوئیدراتهاچون چربیها سوختن از حاصل

شود کربس سیکل وارد تواند نمیترکیب همدیگر وبا میشود جمع

میکند ستونی ترکیبات .وتولیدایجاد؟ مواقع

های 1- وگرسنگی ها قحطی در.شدید

-2 دیابت در -3-4

1- اسید استیک .استواسید -2 بوتیریک هیدرکسی .بتا

استون -3متابولیسم در اختاللی هرگاه

کوآ استیل شود ایجاد کربوئیدراتهاچون چربیها سوختن از حاصل

شود کربس سیکل وارد تواند نمیترکیب همدیگر وبا میشود جمع

میکند ستونی ترکیبات .وتولیدایجاد؟ مواقع

های -1 وگرسنگی ها قحطی در.شدید

دیابت -2 در3- 4-

Fatty acid are synthesized and degraded by different pathways.

Synthesis takes place in the cytosol.Intermediates are attached to the acyl carrier protein (ACP).In higher organisms, the active sites for the synthesis reactions are all on the same polypeptide.The activated donor in the synthesis is malonyl–ACP.Fatty acid reduction uses NADPH + H+.Elongation stops at C16 (palmitic acid)

Fatty acid are synthesized and degraded by different pathways.

Synthesis takes place in the cytosol.Intermediates are attached to the acyl carrier protein (ACP).In higher organisms, the active sites for the synthesis reactions are all on the same polypeptide.The activated donor in the synthesis is malonyl–ACP.Fatty acid reduction uses NADPH + H+.Elongation stops at C16 (palmitic acid)

Fatty Acid Synthesis.Fatty Acid Synthesis.

بیو سنتز اسید های چرب

بیو سنتز اسید های چرب

The intermediates in fatty acid synthesis are covalently linked to the acyl carrier protein (ACP)

The intermediates in fatty acid synthesis are covalently linked to the acyl carrier protein (ACP)

Acyl Carrier ProteinAcyl Carrier Protein

Acetyl–CoA is synthesized in the mitochondrial matrix, whereas fatty acids are synthesized in the cytosol

Acetyl–CoA units are shuttled out of the mitochondrial matrix as citrate:

Acetyl–CoA is synthesized in the mitochondrial matrix, whereas fatty acids are synthesized in the cytosol

Acetyl–CoA units are shuttled out of the mitochondrial matrix as citrate:

Citrate ShuttleCitrate Shuttle

Eicosanoid horomones are synthesized from arachadonic acid (20:4).

Prostaglandins20-carbon fatty acid containing 5-carbon ringProstacyclinsThromboxanes

Leukotrienescontain three conjugated double bonds

Eicosanoid horomones are synthesized from arachadonic acid (20:4).

Prostaglandins20-carbon fatty acid containing 5-carbon ringProstacyclinsThromboxanes

Leukotrienescontain three conjugated double bonds

Eicosanoid HormonesEicosanoid Hormones

6.2 Eicosanoid Hormones6.2 Eicosanoid Hormones

Cholesterol: What is it?Cholesterol: What is it?

Cholesterol is a fatty steroid made primarily in the liver of most animals and humans. It is an integral component in the synthesis of hormones, can also be found in cell walls of animals and humans.

Isolated cholesterol is a white, flaky solid that is insoluble in aqueous environments.

H O

Cholesterol

بیو سنتز کلسترو

ل

بیو سنتز کلسترو

ل

بیو سنتز کلسترولبیو سنتز کلسترول

statin drugs&Cholesterol statin drugs&Cholesterol -

دفع کلسترولدفع کلسترول

cholesterol.

متابولیسم پروتئین ها و

اسیدهای امینه

متابولیسم پروتئین ها و

اسیدهای امینه

تجزیهتجزیه

Dietary protein Polypeptide Mixture Aminoacid &

oligopepti

بافتی های پروتئین Aminoacid انواع Aminoacid

Dietary protein Polypeptide Mixture Aminoacid &

oligopepti

بافتی های پروتئین Aminoacid انواعAminoacid

PepsinPepsin

BloodBloodسنتزسنتز

AminopeptidaseTripeptidasedipeptidase

AminopeptidaseTripeptidasedipeptidase

Trypsin,Chymotrypsincarboxypeptid

ase

Trypsin,Chymotrypsincarboxypeptid

ase

KidneyKidney

NH3NH3

R-CH-COOH

NH2

R-CH-COOH

NH2 DeaminationDeamination

اسید اسید کتو کتو

Non Protein Nitrogen (NPN)Non Protein Nitrogen (NPN)

کربس ATPسیکل

UreaUrea

NH4NH4UrineUrine

LiverLiver

آمینه اسیدهای آمینه متابولیسم اسیدهای متابولیسم

متابولیسم چرخه وارد طریق ازسه امینه اسیدهای:میشوند

-1 . غذا . 2ازطریق پروتئینها- انحالل - 3ازطریقبدن در سنتز

آمینه های اسید :واکنشهای -1 دکربوکسیله و دآمینه شامل عمومی .واکنشهای

آمین –2 عامل .سرنوشتآمینه –3 اسید کربنی ریشه .سرنوشت

متابولیسم چرخه وارد طریق ازسه امینه اسیدهای:میشوند

1- . غذا . 2ازطریق پروتئینها- انحالل - 3ازطریقبدن در سنتز

آمینه های اسید :واکنشهایدکربوکسیله -1 و دآمینه شامل عمومی .واکنشهای

آمین – 2 عامل .سرنوشتآمینه – 3 اسید کربنی ریشه .سرنوشت

شدن شدن Deamination دآمینه Deamination دآمینه

1-Transaminases: I- (AST) aspartate aminotransferase Serum Glutamate:oxaloacetate transaminase [SGOT]

II-Serum Glutamate:pyruvate transaminase [SGPT]alanine aminotransferase(ALT)

1-Transaminases: I- (AST) aspartate aminotransferase Serum Glutamate:oxaloacetate transaminase [SGOT]

II-Serum Glutamate:pyruvate transaminase [SGPT]alanine aminotransferase(ALT)

Pyridoxal phosphate

(PLP)-

Pyridoxal phosphate

(PLP)-

a s p a r t a t e - k e t o g l u t a r a t e o x a l o a c e t a t e g l u t a m a t e

A m i n o t r a n s f e r a s e ( T r a n s a m i n a s e )

C O O

C H 2

C H 2

C

C O O

O

C O O

C H 2

HC

C O O

N H 3+

C O O

C H 2

C H 2

HC

C O O

N H 3+

C O O

C H 2

C

C O O

O + +

a l a n i n e - k e t o g l u t a r a t e p y r u v a t e g l u t a m a t e

A m i n o t r a n s f e r a s e ( T r a n s a m i n a s e )

C O O

C H 2

C H 2

C

C O O

O

C H 3

HC

C O O

N H 3+

C O O

C H 2

C H 2

HC

C O O

N H 3+

C H 3

C

C O O

O + +


2-Glutamate dehydrogenase [GluDH]2-Glutamate dehydrogenase [GluDH]


3- L –amioacid oxidase :

R-CH –COOH R-CO-COOH NH2 H2O NH3

3- L –amioacid oxidase :

R-CH –COOH R-CO-COOH NH2 H2O NH3


اکسیاتیو غیر شدن Non Oxidativ دآمینهDeamination glutaminase glutamine + H2O + glutamate

NH3

Asparginase + Aspargine +H20 Asparticacid

NH3

اکسیاتیو غیر شدن Non OxidativدآمینهDeamination glutaminaseglutamine + H2O glutamate +

NH3

AsparginaseAspargine +H20 Asparticacid +

NH3

Serine Dehydratase catalyzes: serine pyruvate + NH3

آمین عامل آمین سرنوشت عامل سرنوشت

سرنوشت ریشه کربنیسرنوشت ریشه کربنی

به تبدیل آنها کربنی ریشه که ای امینه های اسید اسیداز پیرویک یکی کربس یا سیکل های به واسطه شود

امینه های اسید ساز یا گلیکوژنیکآنها میگویند قند .

به تبدیل آنها کربنی ریشه که ای امینه های استیل اسیدکوا استواستیل یا های کوا اسید آنها به امینه شودساز یاستون میگویند کتوژنیک .

به تبدیل آنها کربنی ریشه که ای امینه های اسید اسیداز پیرویک یکی کربس یا سیکل های به واسطه شود

امینه های اسید ساز یا گلیکوژنیکآنها میگویند قند .

به تبدیل آنها کربنی ریشه که ای امینه های استیل اسیدکوا استواستیل یا های کوا اسید آنها به امینه شودساز یاستون میگویند کتوژنیک .

Acetoacetyl CoA

Glucose

Phosphoenol-pyruvate

Asparagine

Aspartate

TyrosinePhenylalanin

eIsoleucine

ValineMethionin

eThreonine

Oxaloacetate

Fumarate

SuccinylCoA

-keto-glutarat

e

Citrate

Pyruvate

GlycineCysteineSerineAlanine

ThreonineTryptopha

n

Isoleucine

Leucine

Acetyl CoA

GlutamateGlutamineHistidineProline

Arginine

LeucineLysine

PhenylalanineTyrosine

Tryptophan

Fates of the carbon skeletons of amino acids. Glucogenic amino acids are shaded red, ketogenic amino acids are shaded

green and glucoketogenic amino acids are shaded blue.3232

Histidine Metabolism: Histamine Formation

N

NH

CH2CHCO2-

NH3

+

N

NH

CH2CH2NH2

Histidine Histamine

Histidinedecarboxylase

CO2

Histamine:• Synthesized in and released by mast cells• Mediator of allergic response: vasodilation, bronchoconstriction (H1 receptors)

• H1 blockers: Diphenhydramine (Benadryl) Loratidine (Claritin)

• Stimulates secretion of gastric acid (H2 receptors)

• H2 blockers: Cimetidine (Tagamet); ranitidine (Zantac)

تیروزین و آالنین فنیل تیروزین متابولیسم و آالنین فنیل متابولیسم

CH2CHCO2-

NH3+

CH2CHCO2-

NH3+

HO

Phenylalanine(Essential)

Tyrosine

(Phenylalaninehydroxylase)

DOPA

NADPH + H+

T3& T4

پروتئینها انواع سنتزبافتی

Alkaptonuria ×

تیروئید + ید

انواع سنتزبافتی پروتئینها

کتون فنیلها

CH2CHCO2-

NH3+

HO

HO CH2CHCO2-

NH3+

HO

HO

Epinephrine(Adrenaline)

Norepinephrine

Albinism

Tyrosine

Homogentisate(الکاپتون

Phenylketonuria (PKU) Disease

Homogentisatedioxygenase

Melanine

Fumarate + acetoacetate

Tyrosinase

کربس ATPسیکل

3535

Catecholamine BiosynthesisCatecholamine Biosynthesis

CH2CHCO2-

NH3+

HO

CH2CHCO2-

NH3+

HO

HO

CH2CH2NH2

HO

HO

CHCH2NH2

HO

HO

OH

CHCH2NHCH3

HO

HO

OH

Tyr hydroxylase

O2

Tyrosine Dihydroxyphenylalanine (DOPA)

Dopamine

DOPAdecarboxylase CO2

Dopaminehydroxylase

Norepinephrine

Catechol

Epinephrine(Adrenaline)

SAM

S-Adenosyl-homocysteine

Methyl transferase

DOPA, dopamine, norepinephrine,and epinephrine are all neurotransmitters

3636

L-DOPA in ParkinsonismL-DOPA in Parkinsonism

Blood Brain

Blood Brain Barrier

L-DOPA L-DOPA Dopamine

Dopamine

HO

HO CH2-C-CO2H

CH3

NHNH2Carbidopa

Blocks

Parkinsonism associated with dopamine in brain through loss of

neurons in basal ganglia.Carbidopa + L-DOPA

3737

Monoamine Oxidase (MAO)Monoamine Oxidase (MAO)

MAO(in mitochondria)

R R’OH H Norepi

OH CH3 EpiH H Dopamine

CHCH2NHR'

HO

HO

R

CHCHO

HO

HO

R

CHCO2H

HO

HO

RUrinary metabolite

MAO inhibitors (e.g., tranylcypromine) are useful in the treatment of depression

Brain levels of dopamine and norepi.; also serotonin

Aldehydedehydrogenase

R=OH Vanillylmandelic acid (VMA)R=H Homovanillic acid (HVA)

3838

TyramineTyramineOH

CH2CH2NH2

Tyramine

OH

CH2CHO

MAO

• Tyramine found naturally in several types of cheese; also beer and red wine.

• Tyramine intake can cause hypertensive crisis in persons taking a MAO inhibitor ( norepi release)

( blood pressure)

3939

Catechol-O-Methyl Transferase (COMT)

Catechol-O-Methyl Transferase (COMT)

CHCH2NHR'

HO

HO

R

CHCH2NHR'

HO

CH3O

R

COMT

Inactive metabolite

SAM S-Adenosyl-homocysteine

• COMT found in cytoplasm• Terminates activity of catecholamines

• Catecholamine excretion products result from combined actions of MAO and COMT

• Inhibitors of COMT (e.g., tolcapone) useful in Parkinson’s disease

Active catecholamine

4040

Melanin FormationMelanin Formation

CH2CHCO2-

NH3

O

O

+

CH2CHCO2-

NH3+

HO

HO

Highly colored polymeric

intermediates

Melanin(Black polymer)

Tyr hydroxylase

DOPA

Dopaquinone

CH2CHCO2-

NH3+

HO

Tyrosine

Tyrosinase

Melanin formed in skin (melanocytes), eyes, and hairIn skin, protects against sunlight

Albinism: genetic deficiency of tyrosinase

O2

NH

CH2CHCO2-

NH3

+

NH

CH2CHCO2-

NH3

HO

+

NH

CH2CH2NH2

HO

Tryptophan(Trp)

Indole ring

Trphydroxylase

O2

5-Hydroxy-tryptophan

Decarboxylase

CO2 5-Hydroxy-tryptamine (5-HT);Serotonin

NH

CH2CHO

HO

NH

CH2CO2H

HO

MAO

Dehydrogenase

5-Hydroxyindole acetic acid (5-HIAA) (Urine)

B3

N

CO2H

4242

Amino Acids Formed From -Ketoglutarate

Amino Acids Formed From -Ketoglutarate

O-O2CCH 2CH2CCO 2

-

NH3+

-O2CCH 2CH2CHCO 2-

NH3+O

H2NCCH 2CH2CHCO 2-

Transamination or Glutamate

dehydrogenase

-Keto-glutarate

Glutamate

Glutamine

Glutamine synthase

N

H H

CO2-

+

4 Steps

Proline

NH3+

+H3NCH2CH2CH2CHCO 2

- Ornithine

5 Steps

Arginine

Urea Cycle

NH3+NH2

H2N=C-HNCH2CH2CH2CHCO 2-

+

Guanidino group

4343

Synthesis of Nitric OxideSynthesis of Nitric Oxide

NH3+NH2

H2N=C-HNCH2CH2CH2CHCO 2-

+

NH3+

NH2CONHCH2CH2CH2CHCO 2- + NO

Nitric oxide synthase (NOS)

Arginine

Citrulline

4444

Nitric OxideNitric Oxide

• Cell messenger• Implicated in a wide range of physiological

and pathophysiological events:• Vasodilation:

• Activates guanylyl cyclase cGMP• Nitroglycerin Glycerin + NO

• Sildenafil (Viagra): in vascular smooth muscle:

NO cGMP GMPPhospho-

diesterase-5Blocks

4545

Formation of SerineFormation of Serine

OHH

CH2OPO3-2

C

CO 2-

CH2OPO3-2

CO 2-

C=O

NH3+H

CH2OPO3-2

C

CO 2-

NH3+H

CH2OH

CO 2-

C

Glucose Glycolysis

3-Phospho-glycerate

3-Phospho-hydroxypyruvate

3-PhosphoserineSerine (Ser)

Pyruvate

Dehydrogenase

NAD+ NADH + H+

Glutamate

-Ketoglutarate

Transaminase

Phosphatase

3 Steps

Inhibits

4646

Conversion of Serine to GlycineConversion of Serine to Glycine

N

N

N

NH2N

OH

CH2NHR

H

H

NH

N CH2

NH2C

Folate

Tetrahydrofolate (FH4)

Dihydrofolate reductase

N5, N10-Methylene FH4

NH3+H

CH2OH

CO 2-

C Serine

NH3+H

H

CO 2-

CGlycine

Serine hydroxymethyltransferase (PLP-dep.)

Key intermediatein biosynthesis of

purines andformation of

thymine Important in biosynthesis of heme,

porphyrins, and purines

4747

Sulfur-Containing Amino AcidsSulfur-Containing Amino Acids

NH3+

CH3SCH2CH2CHCO 2-

NH3+

HSCH2CH2CHCO 2-

NH3+

CH2CHCO2-

NH3+

SCH2CH2CHCO 2-NH3

+

HSCH2CHCO 2-

OH

CH3CHCH 2CO2-

Methionine(Essential)

L-Homocysteine

MethionineSynthase

(Vit. B12-dep.)+ FH4

+ 5-Methyl FH4

NH3+H

CH2OH

CO 2-

C Serine

Cystathionine

Cystathionine-synthase(PLP-dep.)

Cystathioninelyase

Cysteine(Non-essential)

+

-Hydroxy-butyrate

4848

HomocysteineHomocysteine

Homocysteinuria• Rare; deficiency of cystathionine -synthase

• Dislocated optical lenses• Mental retardation

• Osteoporosis• Cardiovascular disease death

High blood levels of homocysteine associated withcardiovascular disease

• May be related to dietary folate deficiency• Folate enhances conversion of

homocysteine to methionine

4949

Methionine Metabolism: Methyl DonationMethionine Metabolism: Methyl Donation

N

N N

N

O

OHOH

-O2CCHCH2CH2-S-H2C

NH2

NH3+ CH3

+NH3

+

CH3SCH2CH2CHCO 2-

N

N N

N

O

OHOH

-O2CCHCH2CH2-S-H2C

NH2

NH3+

N

N N

N

O

OHOH

H3NCH2CH2CH2-S-H2C

NH2

CH3

+

S-Adenosyl methioninesynthase

ATP

S-Adenosyl Methionine

(SAM)

S-Adenosyl homocysteine

Methyl-transferases

Decarboxylated SAM

SAM Decarboxylase

CO2

Methionine

R-H

R-CH3

+

5050

PolyaminesPolyamines• Spermidine and spermine found in virtually

all procaryotic and eucaryotic cells

• Precise role undefined• Bind to nucleic acids

• Inhibition of biosynthetic pathway:

H2NNH2

CO2H

CHF2

-Difluoromethyl-ornithine (DFMO)

(Eflornithine) - inhibits ODC;used to treat

Pneumocystis carinii infectons

5151

Polyamine BiosynthesisPolyamine Biosynthesis

NH3+

H3NCH2CH2CH2CHCO 2-

+

H3NH

H

HN

H

N NH3

++++

H3NNH3

++

Ornithine(from urea cycle)

Putrescine

CO2

Ornithinedecarboxylase

(ODC)(PLP-dep.)

DecarboxylatedSAM

Spermidine synthase

5’-Methylthio-adenosine

H3NNH

NH3

H

+++

Spermidine

Spermine

DecarboxylatedSAM

Spermine synthase

5’-Methylthio-adenosine

5252

Creatine and CreatinineCreatine and Creatinine

NH3+NH2

+H2N=C-HNCH2CH2CH2CHCO 2

-

Arginine Glycine Ornithine

Arginine-glycinetransamidinase

(Kidney)NH2

H2N=C-HNCH2CO 2-

+

Guanidoacetate

NHPO3-2

CH3

+H2N=C-NCH2CO 2

-

GuanidoacetateMethyltransferase

(Liver)

SAM + ATP

S-Adenosyl-homocysteine

+ ADP

Phosphocreatine

N

NH

CH3

HN

O

Creatinine(Urine) Non-enzymatic

(Muscle)

NH2

CH3

H2N=C-NCH2CO 2-

+

Creatine kinase(Muscle)

ATP

Creatine ADP + Pi

5353

Creatine and Creatinine Creatine and Creatinine

Creatine:• Dietary supplement

• Used to improve athletic performance

Creatinine:• Urinary excretion generally constant;

proportional to muscle mass

Creatinine Clearance Test:• Compares the level of creatinine in urine (24 hrs.)

with the creatinine level in the blood• Used to assess kidney function

• Important determinant in dosing of several drugs in patients with impaired renal function

ساختمان نوکلئوتید ها و اسیدهای

نوکلئیک

ساختمان نوکلئوتید ها و اسیدهای

نوکلئیک

Nucleic Acid StructureNucleic Acid Structure

A. Structure of nucleotidesB. Nitrogenous basesC. Pentose sugarsD. NucleosidesE. NucleotidesF. Nucleotide chainsG. Structure of B-DNA

A. Structure of nucleotidesB. Nitrogenous basesC. Pentose sugarsD. NucleosidesE. NucleotidesF. Nucleotide chainsG. Structure of B-DNA

ساختمان نوکلئوتید ها و اسیدهای نوکلئیک

A. Structure of NucleotidesA. Structure of Nucleotides

•A nucleotide is composed ofA nitrogenous base:Purines:Adenine& GuaninePyrimidines:Cytosine &Thymine&Uracil

A pentose sugarA phosphate group

•A nucleotide is composed ofA nitrogenous base:Purines:Adenine& GuaninePyrimidines:Cytosine &Thymine&Uracil

A pentose sugarA phosphate group

Nucleosides & NucleotidesNucleosides & Nucleotides

•NucleosideA pentose sugar molecule with a nitrogenous base attached to the 1´ carbonNucleosides are named by using the root of the base name, plus the suffix “-osine” (for purines) or “-idine” (for pyrimidines)Nucleosides with deoxyribose sugars are designated with the prefix “deoxy-”

•NucleosideA pentose sugar molecule with a nitrogenous base attached to the 1´ carbonNucleosides are named by using the root of the base name, plus the suffix “-osine” (for purines) or “-idine” (for pyrimidines)Nucleosides with deoxyribose sugars are designated with the prefix “deoxy-”

• Base + sugar + phosphate(s) nucleotide

• Base + sugar nucleoside

• DNA and RNA are large macromolecules with several levels of complexity

• Nucleotides form the repeating units

• Phosphodiester bonds link nucleotides to form a strand

• Two strands interact to form a double helix

• The double helix interacts withproteins resulting in 3-D structuresin the form of chromatin

• DNA and RNA are large macromolecules with several levels of complexity

• Nucleotides form the repeating units

• Phosphodiester bonds link nucleotides to form a strand

• Two strands interact to form a double helix

• The double helix interacts withproteins resulting in 3-D structuresin the form of chromatin

NUCLEIC ACID STRUCTURE NUCLEIC ACID STRUCTURE

3D structure

Nucleotide Polymerization Reaction: Phosphodiester Bond Formation

Nucleotide Polymerization Reaction: Phosphodiester Bond Formation

Base Pairing Key to DNA StructureBase Pairing Key to DNA Structure

Features of the DNA Double HelixFeatures of the DNA Double Helix

NH2

T

2 nm

One nucleotide0.34 nm

One completeturn 3.4 nm

O

O

HH

NN

H

H

HHOOO

OPO–

NH2

HN

N

NH

N

HH

H

OH

HHOOO

O–

PO–

HH

H

HHOOO

OPO–

NH2

O

O

H H

NN

H2N

HN

N

NH

N

H H

H

HHO

OOO–

PO

H H

H

HHO OO

O–

PO

H N

NH

N

N

H H

H

HHO

OOO–

PO–

H2N

HO5end 3end

3hydroxyl3end 5 end

5phosphate

TA

T A

T AP

PP

P

P

S

S

S

S

SS

S

S

A

C G

G

C G

C G

G

G

C

C

G C

GC

G C

C

P

PS

P

PP

P

P

S

SS

S

S

PP

P

P

PP

P

P

S

S SS

S

S

S

S

SP

S

S

P

PP

S

SS

SP

CH2

CH2

CH2

H2N

CH2

CH2

CH2

A

P

S

P

P

H

CH3H

NNHO

O

Space-filling model of DNA

Ball-and-stick model of DNA

Minorgroove

Majorgroove

Minorgroove

Majorgroove

Features of the DNA Double HelixFeatures of the DNA Double Helix

BDNA:

هلیکس آن راست گرد می باشد.

جفت ب�از وج�ود 10 در ه�ر دور آن دارد.

می باشد.Å4/3طول هر دور آن

Å20 ( nmفاص�له دو رش�ته آن است.(2

هلیکس مح�ور ب�ه نس�بت بازه�ا بصورت عمود قرار می گیرند.

ن�وع ش�یار دی�ده 2در س�اختمان آن می شود:

major grove - minor grove

: ب�زرگ ش�یار Å22 ( nmطول 2/2)

: کوچ�ک ش�یار Å12 ( nmطول 2/1)

DNADNAانواعانواعDNADNAانواعانواع

ADNA: هلیکس آن راست گرد می باشد.

جفت باز وجود دارد.11 در هر دور آن

زاوی�ه ب�ه مح�ور هلیکس 23بازه�ا نس�بت درجه دارند.

در س�اختمان آن فق�ط ی�ک ن�وع ش�یار دی�ده می شود.

در صورت کم بودن رطوبت محیط یا زیادبوجود ADNA و ZDNAبودن نمک محیط

می آیند.

ZDNA: هلیکس آن چپ گرد می باشد.

جفت باز وجود دارد.12 در هر دور آن

زاوی�ه هلیکس مح�ور ب�ه نس�بت 180بازه�ا درجه دارند.

در س�اختمان آن فق�ط ی�ک ن�وع ش�یار دی�ده می شود.

DNADNAانواعانواعDNADNAانواعانواع

ADNA BDNA

Comparison of A, B, and Z forms of DNA

Comparison of A, B, and Z forms of DNA

9-57

• The primary structure of an RNA strand is much like that of a DNA strand

• RNA is made as a single strand only, however it may form a double stranded

structures

• RNA strands can be a 10s to1000s of nt in length

• RNA is made from a DNA template - only one of the two strands of a DNA helix is used as

the template

• RNA contains uracil rather than thymine

Messenger RNA=mRNATransfer RNA=tRNA

Ribosomal RNA=rRNA

RNA StructureRNA Structure

9-58Figure 9.22

Messenger RNAsMessenger RNAs

• Contain protein coding informationATG start codon to UAA, UAG, UGA Stop Codon A cistron is the unit of RNA that encodes one polypeptide chain

• Base pairing/3D structure is the exceptionCan be used to regulate RNA stability termination, RNA editng, RNA splicing

• Contain protein coding informationATG start codon to UAA, UAG, UGA Stop Codon A cistron is the unit of RNA that encodes one polypeptide chain

• Base pairing/3D structure is the exceptionCan be used to regulate RNA stability termination, RNA editng, RNA splicing

Transfer RNA (tRNA)Transfer RNA (tRNA)

• Is a single strand folded into a cloverleaf shape

•Has a specific site to which specific amino acids can attach

•There is a different type of tRNA for each type of amino acid

•Each type of tRNA has three bases which are specific to the type of amino acid which will attach

•These three bases are called the anticodon

• Is a single strand folded into a cloverleaf shape

•Has a specific site to which specific amino acids can attach

•There is a different type of tRNA for each type of amino acid

•Each type of tRNA has three bases which are specific to the type of amino acid which will attach

•These three bases are called the anticodon

GCA

tRNA Specific amino acid attaches

Anticodon – specific to the amino acid which attaches to this tRNA molecule

More simply drawn

متابولیسم اسیدهای نوکلئیک

Nucleoprotein

Nucleic acid Protein

Nucleotide

NucleosidePhosphate

Base Ribose

Nucleotidase

Nucleosidase

Degradation of nucleic acid

In stomach Gastric acid and pepsin

In small intestine Endonucleases: RNase and DNase

Significances of nucleotidesSignificances of nucleotides

1. Precursors for DNA and RNA synthesis

2. Essential carriers of chemical energy, especially ATP

3. Components of the cofactors NAD+, FAD, and coenzyme A

4. Formation of activated intermediates such as UDP-glucose and CDP-diacylglycerol.

5. cAMP and cGMP, are also cellular second messengers.

1. Precursors for DNA and RNA synthesis

2. Essential carriers of chemical energy, especially ATP

3. Components of the cofactors NAD+, FAD, and coenzyme A

4. Formation of activated intermediates such as UDP-glucose and CDP-diacylglycerol.

5. cAMP and cGMP, are also cellular second messengers.

There are two pathways leading to nucleotides

There are two pathways leading to nucleotides

• De novo synthesis: The synthesis of nucleotides begins with their metabolic precursors: amino acids, ribose-5-phosphate, CO2, and one-carbon units.

• Salvage pathways: The synthesis of nucleotide by recycle the free bases or nucleosides released from nucleic acid breakdown.

• De novo synthesis: The synthesis of nucleotides begins with their metabolic precursors: amino acids, ribose-5-phosphate, CO2, and one-carbon units.

• Salvage pathways: The synthesis of nucleotide by recycle the free bases or nucleosides released from nucleic acid breakdown.

§ 2.1 De novo synthesis§ 2.1 De novo synthesis

• Site: in cytosol of liver, small intestine and thymus

• Characteristics: a. Purines are synthesized using 5-

phosphoribose(R-5-P) as the starting material step by step.

b. PRPP(5-phosphoribosyl-1-pyrophosphate) is active donor of R-5-P.

c. AMP and GMP are synthesized further at the base of IMP(Inosine-5'-Monophosphate).

• Site: in cytosol of liver, small intestine and thymus

• Characteristics: a. Purines are synthesized using 5-

phosphoribose(R-5-P) as the starting material step by step.

b. PRPP(5-phosphoribosyl-1-pyrophosphate) is active donor of R-5-P.

c. AMP and GMP are synthesized further at the base of IMP(Inosine-5'-Monophosphate).

Purine Nucleotide SynthesisPurine Nucleotide Synthesis

Purine Nucleotide SynthesisPurine Nucleotide Synthesis

OH

H

H

CH2

OH OH

H HO

O2-O3P

-D-Ribose-5-Phosphate (R5P)

O

H

H

CH2

OH OH

H HO

O2-O3P

5-Phosphoribosyl--pyrophosphate (PRPP)

P

O

O

O P

O

O

O

ATP

AMP

RibosePhosphatePyrophosphokinase

H

NH2

H

CH2

OH OH

H HO

O2-O3P

-5-Phosphoribosylamine (PRA)

AmidophosphoribosylTransferase

Glutamine + H2O

Glutamate + PPi

Inosine Monophosphate (IMP)

HN

HCN

C

CC

N

CH

N

O

4

5

HH

CH2

OH OH

H HOO2-O3P

SS

H2OMg2+

NADPH + H+NADP+

SHSH

thioredoxin

ribonucleotide reductase

NDP£¨N=A, G, C, U£©

dNDP

dNTP

ATP

ADP

kinase

O BaseCH2

HOH

OP PO BaseCH2

OHOH

OP P

thioredoxin

thioredoxin reductase

FAD

Deoxyribonucleotide synthesis at the NDP level

Purine nucleotide biosynthesis is regulated by feedback inhibition

Purine nucleotide biosynthesis is regulated by feedback inhibition

Purine Salvage PathwayPurine Salvage Pathway

N

NN

N

NH2

O

Guanine

N

N N

O

N

Hypoxanthine

O

OHHO

2-O3POH2C

N

N N

O

N

IMP

O

OHHO

2-O3POH2C

N

NN

N

NH2

O

GMP

.

.

Adenine AMP

PRPP PPi

adenine phosphoribosyl transferase

PRPP PPi

hypoxanthine-guaninephosphoribosyl transferase

(HGPRT)

Absence of activity of HGPRT leads to Lesch-Nyhan syndrome.

پورین بازهای دفع و پورین تجزیه بازهای دفع و تجزیه

-

GoutImpaired excretion or overproduction of uric acid

Uric acid crystals precipitate into joints (Gouty Arthritis), kidneys, ureters (stones)

Lead impairs uric acid excretion – lead poisoning from pewter drinking goblets

Fall of Roman Empire?Xanthine oxidase inhibitors inhibit production of uric acid, and treat gout

Allopurinol treatment – hypoxanthine analog that binds to Xanthine Oxidase to decrease uric acid production

The uric acid and the gout

Uric acid Over 8mg/dl, in the plasma

Gout, Urate crystallization in joints, soft tissue, cartilage and

kidney

Hypoxanthine

Xanthine Out of body

In urine

Diabetese nephrosis

……

ALLOPURINOL IS A XANTHINE OXIDASE INHIBITORALLOPURINOL IS A XANTHINE OXIDASE INHIBITOR

A SUBSTRATE ANALOG IS CONVERTED TO AN INHIBITOR, IN THIS CASE A “SUICIDE-INHIBITOR”

Element source of pyrimidine base

Element source of pyrimidine base

N

CN

C

CC

12

34

5

6Asp

CO2

Gln

•Carbamoyl phosphate synthetase(CPS) exists in 2 types: •CPS-I, a mitochondrial enzyme, is dedicated to the urea cycle and

arginine biosynthesis. •CPS-II, a cytosolic enzyme, used here. It is the committed step in

animals.

synthesis of carbamoyl phosphatesynthesis of carbamoyl phosphate

2 ATP + HCO3- + Glutamine + H2O

CO

O PO3-2

NH2

Carbamoyl Phosphate

HN

CNH

C

CHC

COOO

O

Orotate

HN

CN

CH

CHC

O

O

HH

CH2

OH OH

H HO

O2-O3P

Uridine Monophosphate(UMP)

2 ADP +Glutamate + Pi

CarbamoylPhosphateSynthetase II

AspartateTranscarbamoylase(ATCase)

Aspartate

Pi

H2O

Dihydroorotase

PRPP PPi

Orotate PhosphoribosylTransferase

Pyrimidine Synthesis

CMP

TMP

Synthesis of UMP from carbamoyl phosphate

5. Regulation of de novo synthesis5. Regulation of de novo synthesis

carbamoyl phosphate

carbamoyl aspartate

UMP

ATP + CO2 + Gln

PRPP

UTP CTP

ATP + R-5-P

purine nucleotide

pyrimidine nucleotide

پیریمیدین بازهای ودفع پیریمیدین تجزیه بازهای ودفع تجزیه

Thymidine γ aminoisobutyrate

CO2+NH3 CytosineUracil β alanine

+CO2+NH3

γ aminoisobutyrate Succinyl COA

Thymidine γ aminoisobutyrate

CO2+NH3 CytosineUracil β alanine

+CO2+NH3

γ aminoisobutyrate Succinyl COA

Pyrimidine Catabolism Pyrimidine Catabolism

enzyme specification.

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