متابولیسم 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
Introduction
The lipases break the triacylglycerols down to fatty acids and glycerol
The fatty acids are transportred in the blood by serum albumin
Breakdown of Triacylglycerols
Transport into Mitochondrial Matrix
Fatty acid oxidation
Acyl-CoA Synthetase
Acyl-CoA Synthetase
درهرمرحله یک FADH2تولید میشودکه در زنجیر انتقال الکترون 2ATPمیدهد .
درهرمرحله یک NADH2 تولید میشودکه در زنجیر انتقال الکترون 3ATPمدهید.
درهرمرحله یک استیل کوآنزیم آ تولید میشودکه در سیکل کربس 12ATPمیدهد.
پس در هر مرحله بتااکسیداسیون 17ATP تولید میشود.
اگر اسید چرب 2n کربن در ساختمان آن باشد واکنشهای بتا اکسیداسیون n-1مرتبه تکرار میشود. بنابراین خواهیم داشت.
چون در پایان دو استیل کوآداریم ودومی 12ATP تولید میکند
ATP=17(n-1)+12
وچون در ابتدا 2ATPمصرف شد .بنابراین:
ATP=17(n-1)+10
ATP=17n – 7
اگر تعداد کربن اسید چرب فرد باشد . 3کربن ازاسید چرب کم کرده وطبق بالا عمل نموده ودر پایان 6ATP به آن اضافه میکنیم.
اگر تعداد کربن اسید چرب فرد باشد . 3کربن ازاسید چرب کم کرده ازرابطه زیر استفاده میکنیم . ATP= 17n-1
ATP Yield
(جدید)محاسبه انرژی سوختن چربیها
درهرمرحله یک FADH2تولید میشودکه در زنجیر انتقال الکترون 1/5ATPمیدهد .
درهرمرحله یک NADH2 تولید میشودکه در زنجیر انتقال الکترون 2/5ATPمدهید.
درهرمرحله یک استیل کوآنزیم آ تولید میشودکه در سیکل کربس 10ATPمیدهد.
پس در هر مرحله بتااکسیداسیون 14ATP تولید میشود.
اگر اسید چرب 2n کربن در ساختمان آن باشد واکنشهای بتا اکسیداسیون n-1مرتبه تکرار میشود. بنابراین خواهیم داشت.
چون در پایان دو استیل کوآداریم ودومی 10ATP تولید میکند
ATP=14(n-1)+10
وچون در ابتدا 2ATPمصرف شد .بنابراین:
ATP=14(n-1)+8
ATP=14n – 6
اگر تعداد کربن اسید چرب فرد باشد . 3کربن ازاسید چرب کم کرده وطبق بالا عمل نموده ودر پایان 5ATP به آن اضافه میکنیم.
اگر تعداد کربن اسید چرب فرد باشد . 3کربن ازاسید چرب کم کرده ازرابطه زیر استفاده میکنیم . ATP= 14n-1
Ketone 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)
ترکیبات ستونی
1-استو استیک اسید.
2- بتا هیدرکسی بوتیریک اسید.
3- استون
هرگاه اختلالی در متابولیسم کربوئیدراتها ایجاد شود استیل کوآ حاصل از سوختن چربیها چون نمی تواند وارد سیکل کربس شود جمع میشود وبا همدیگر ترکیب وتولید ترکیبات ستونی میکند.
مواقع ایجاد؟
1- در قحطی ها وگرسنگی های شدید.
2- در دیابت
3-
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 Synthesis.
بیو سنتز اسید های چرب
استیل کوا کربوکسیلاز
The intermediates in fatty acid synthesis are covalently linked to the acyl carrier protein (ACP)
Acyl 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:
Citrate Shuttle
Eicosanoid horomones are synthesized from arachadonic acid (20:4).
Prostaglandins
20-carbon fatty acid containing 5-carbon ring
Prostacyclins
Thromboxanes
Leukotrienes
contain three conjugated double bonds
Eicosanoid Hormones
6.2 Eicosanoid Hormones
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.
Cholesterol
بیو سنتز کلسترول
بیو سنتز کلسترول
statin drugs&Cholesterol
–
دفع کلسترول
cholesterol.
متابولیسم پروتئین ها و اسیدهای امینه
تجزیه
Dietary protein Polypeptide Mixture Aminoacid &
oligopepti
انواع پروتئین های بافتی Aminoacid Aminoacid
Pepsin
Blood
سنتز
Aminopeptidase Tripeptidase dipeptidase
Trypsin, Chymotrypsin carboxypeptidase
Kidney
NH3
R-CH-COOH NH2
Deamination
کتو اسید
Non Protein Nitrogen (NPN)
سیکل کربس
ATP
Urea
NH4
Urine
Liver
متابولیسم اسیدهای آمینه
اسیدهای امینه ازسه طریق وارد چرخه متابولیسم میشوند:
1- ازطریق غذا. 2- ازطریق انحلال پروتئینها. 3- سنتز در بدن
واکنشهای اسید های آمینه:
1- واکنشهای عمومی شامل دآمینه و دکربوکسیله.
2 – سرنوشت عامل آمین.
3 – سرنوشت ریشه کربنی اسید آمینه.
دآمینه شدن Deamination
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)-
دآمینه شدن Deamination
2-Glutamate dehydrogenase [GluDH]
دآمینه شدن Deamination
3- L –amioacid oxidase :
R-CH –COOH R-CO-COOH
NH2 H2O NH3
دآمینه شدن Deamination
دآمینه شدن غیر اکسیاتیو Non Oxidativ Deamination
glutaminase
glutamine + H2O glutamate + NH3
Asparginase
Aspargine +H20 Asparticacid + NH3
Serine Dehydratase catalyzes: serine pyruvate + NH3
سرنوشت عامل آمین
.
سرنوشت ریشه کربنی
اسید های امینه ای که ریشه کربنی آنها تبدیل به اسید پیرویک یا یکی از واسطه های سیکل کربس شود به آنها اسید های امینه گلیکوژنیک یا قند ساز میگویند.
اسید های امینه ای که ریشه کربنی آنها تبدیل به استیل کوا یا استواستیل کوا شود به آنها اسید های امینه کتوژنیک یاستون ساز میگویند.
Acetoacetyl CoA
Glucose
Phosphoenol-pyruvate
Asparagine
Aspartate
Tyrosine
Phenylalanine
Isoleucine
Valine
Methionine
Threonine
Oxaloacetate
Fumarate
Succinyl
CoA
-keto-glutarate
Citrate
Pyruvate
Glycine
Cysteine
Serine
Alanine
Threonine
Tryptophan
Isoleucine
Leucine
Acetyl CoA
Glutamate
Glutamine
Histidine
Proline
Arginine
Leucine
Lysine
Phenylalanine
Tyrosine
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.
32
Histidine Metabolism: Histamine Formation
Histidine
Histamine
Histidine
decarboxylase
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)
متابولیسم فنیل آلانین و تیروزین
Phenylalanine
(Essential)
Tyrosine
(Phenylalanine
hydroxylase)
DOPA
NADPH + H+
T3& T4
سنتز انواع پروتئینها بافتی
Alkaptonuria ×
تیروئید + ید
سنتز انواع پروتئینها بافتی
فنیل کتون ها
Epinephrine
(Adrenaline)
Norepinephrine
Albinism
Tyrosine
الکاپتون)Homogentisate
Phenylketonuria (PKU) Disease
Homogentisate
dioxygenase
Melanine
Fumarate + acetoacetate
Tyrosinase
سیکل کربس
ATP
35
Catecholamine Biosynthesis
Tyr hydroxylase
O2
Tyrosine
Dihydroxyphenylalanine
(DOPA)
Dopamine
DOPA
decarboxylase
CO2
Dopamine
hydroxylase
Norepinephrine
Catechol
Epinephrine
(Adrenaline)
SAM
S-Adenosyl-
homocysteine
Methyl
transferase
DOPA, dopamine, norepinephrine,
and epinephrine are all neurotransmitters
36
L-DOPA in Parkinsonism
Blood Brain
Blood Brain Barrier
L-DOPA L-DOPA Dopamine
Dopamine
Carbidopa
Blocks
Parkinsonism associated with
dopamine in brain through loss of
neurons in basal ganglia.
Carbidopa + L-DOPA
37
Monoamine Oxidase (MAO)
MAO
(in mitochondria)
R R’
OH H Norepi
OH CH3 Epi
H H Dopamine
Urinary
metabolite
MAO inhibitors (e.g., tranylcypromine) are useful
in the treatment of depression
Brain levels of dopamine and norepi.; also
serotonin
Aldehyde
dehydrogenase
R=OH Vanillylmandelic acid (VMA)
R=H Homovanillic acid (HVA)
38
Tyramine
Tyramine
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)
39
Catechol-O-Methyl Transferase (COMT)
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
40
Melanin Formation
Highly colored
polymeric
intermediates
Melanin
(Black polymer)
Tyr hydroxylase
DOPA
Dopaquinone
Tyrosine
Tyrosinase
Melanin formed in skin (melanocytes), eyes, and hair
In skin, protects against sunlight
Albinism: genetic deficiency of tyrosinase
O2
Tryptophan
(Trp)
Indole ring
Trp
hydroxylase
O2
5-Hydroxy-
tryptophan
Decarboxylase
CO2
5-Hydroxy-
tryptamine (5-HT);
Serotonin
MAO
Dehydrogenase
5-Hydroxyindole acetic
acid (5-HIAA) (Urine)
B3
42
Amino Acids Formed From a-Ketoglutarate
Transamination or
Glutamate
dehydrogenase
a-Keto-
glutarate
Glutamate
Glutamine
Glutamine
synthase
4 Steps
Proline
Ornithine
5 Steps
Arginine
Urea Cycle
Guanidino group
43
Synthesis of Nitric Oxide
+ NO
Nitric oxide synthase (NOS)
Arginine
Citrulline
44
Nitric 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 GMP
Phospho-
diesterase-5
Blocks
45
Formation of Serine
Glucose
Glycolysis
3-Phospho-
glycerate
3-Phospho-
hydroxypyruvate
3-Phosphoserine
Serine (Ser)
Pyruvate
Dehydrogenase
NAD+ NADH +
H+
Glutamate
a-Ketoglutarate
Transaminase
Phosphatase
3 Steps
Inhibits
46
Conversion of Serine to Glycine
Folate
Tetrahydrofolate
(FH4)
Dihydrofolate
reductase
N5, N10-Methylene FH4
Serine
Glycine
Serine hydroxymethyl
transferase (PLP-dep.)
Key intermediate
in biosynthesis of
purines and
formation of
thymine
Important in
biosynthesis of heme,
porphyrins, and purines
47
Sulfur-Containing Amino Acids
Methionine
(Essential)
L-Homocysteine
Methionine
Synthase
(Vit. B12-dep.)
+ FH4
+ 5-Methyl
FH4
Serine
Cystathionine
Cystathionine
b-synthase
(PLP-dep.)
Cystathionine
lyase
Cysteine
(Non-essential)
+
b-Hydroxy-
butyrate
48
Homocysteine
Homocysteinuria
Rare; deficiency of cystathionine b-synthase
Dislocated optical lenses
Mental retardation
Osteoporosis
Cardiovascular disease death
High blood levels of homocysteine associated with
cardiovascular disease
May be related to dietary folate deficiency
Folate enhances conversion of
homocysteine to methionine
49
Methionine Metabolism: Methyl Donation
S-Adenosyl methionine
synthase
ATP
S-Adenosyl
Methionine
(SAM)
S-Adenosyl
homocysteine
Methyl-
transferases
Decarboxylated
SAM
SAM
Decarboxylase
CO2
Methionine
R-H
R-CH3
+
50
Polyamines
Spermidine and spermine found in virtually
all procaryotic and eucaryotic cells
Precise role undefined
Bind to nucleic acids
Inhibition of biosynthetic pathway:
a-Difluoromethyl-
ornithine (DFMO)
(Eflornithine) – inhibits ODC;
used to treat
Pneumocystis carinii infectons
51
Polyamine Biosynthesis
Ornithine
(from urea cycle)
Putrescine
CO2
Ornithine
decarboxylase
(ODC)
(PLP-dep.)
Decarboxylated
SAM
Spermidine
synthase
5’-Methylthio-
adenosine
Spermidine
Spermine
Decarboxylated
SAM
Spermine
synthase
5’-Methylthio-
adenosine
52
Creatine and Creatinine
Arginine
Glycine Ornithine
Arginine-glycine
transamidinase
(Kidney)
Guanidoacetate
Guanidoacetate
Methyltransferase
(Liver)
SAM + ATP
S-Adenosyl-
homocysteine
+ ADP
Phosphocreatine
Creatinine
(Urine)
Non-enzymatic
(Muscle)
Creatine kinase
(Muscle)
ATP
Creatine
ADP
+ Pi
53
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
Nucleic Acid Structure
Structure of nucleotides
Nitrogenous bases
Pentose sugars
Nucleosides
Nucleotides
Nucleotide chains
Structure of B-DNA
ساختمان نوکلئوتید ها و اسیدهای نوکلئیک
A. Structure of Nucleotides
A nucleotide is composed of
A nitrogenous base:Purines:Adenine& Guanine
Pyrimidines:Cytosine &Thymine&Uracil
A pentose sugar
A phosphate group
Nucleosides & Nucleotides
Nucleoside
A pentose sugar molecule with a nitrogenous base attached to the 1´ carbon
Nucleosides 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 with proteins resulting in 3-D structures in the form of chromatin
NUCLEIC ACID STRUCTURE
Nucleotide Polymerization Reaction: Phosphodiester Bond Formation
9-30
Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display
Figure 9.11
Base Pairing Key to DNA Structure
Features of the DNA Double Helix
Space-filling
model of DNA
Ball-and-stick model of DNA
Minor
groove
Major
groove
Minor
groove
Major
groove
Features of the DNA Double Helix
BDNA:
هلیکس آن راست گرد می باشد.
در هر دور آن 10 جفت باز وجود دارد.
طول هر دور آن Å4/3 می باشد.
فاصله دو رشته آن Å20 ( nm 2)است.
بازها نسبت به محور هلیکس بصورت عمود قرار می گیرند.
در ساختمان آن 2 نوع شیار دیده می شود:
major grove – minor grove
طول شیار بزرگ : Å22 ( nm 2/2)
طول شیار کوچک : Å12 ( nm 2/1)
DNAانواع
ADNA:
هلیکس آن راست گرد می باشد.
در هر دور آن 11 جفت باز وجود دارد.
بازها نسبت به محور هلیکس زاویه 23 درجه دارند.
در ساختمان آن فقط یک نوع شیار دیده می شود.
در صورت کم بودن رطوبت محیط یا زیاد بودن نمک محیط ZDNA و ADNA بوجود می آیند.
ZDNA:
هلیکس آن چپ گرد می باشد.
در هر دور آن 12 جفت باز وجود دارد.
بازها نسبت به محور هلیکس زاویه 180 درجه دارند.
در ساختمان آن فقط یک نوع شیار دیده می شود.
DNAانواع
ADNA
BDNA
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=mRNA
Transfer RNA=tRNA
Ribosomal RNA=rRNA
RNA Structure
9-58
Figure 9.22
Messenger RNAs
Contain protein coding information
ATG 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 exception
Can be used to regulate RNA stability termination, RNA editng, RNA splicing
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
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
Nucleoside
Phosphate
Base
Ribose
Nucleotidase
Nucleosidase
Degradation of nucleic acid
In stomach
Gastric acid and pepsin
In small intestine
Endonucleases: RNase and DNase
Significances 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.
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.
§ 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).
Purine Nucleotide Synthesis
Purine Nucleotide Synthesis
Deoxyribonucleotide synthesis at the NDP level
Purine nucleotide biosynthesis is regulated by feedback inhibition
Purine Salvage Pathway
Absence of activity of HGPRT leads to Lesch-Nyhan syndrome.
تجزیه و دفع بازهای پورین
–
Gout
Impaired 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
Out of body
In urine
Diabetese nephrosis
……
ALLOPURINOL IS A XANTHINE OXIDASE INHIBITOR
A SUBSTRATE ANALOG IS CONVERTED TO AN INHIBITOR, IN THIS CASE A “SUICIDE-INHIBITOR”
Element source of pyrimidine base
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 phosphate
Pyrimidine Synthesis
CMP
TMP
5. Regulation of de novo synthesis
تجزیه ودفع بازهای پیریمیدین
Thymidine γ aminoisobutyrate
CO2+NH3
Cytosine
Uracil β alanine +CO2+NH3
γ aminoisobutyrate Succinyl COA
Pyrimidine Catabolism
enzyme specification.
پایان