DETAIL INFORMATION ABOUT Denovo synthesis of fatty acids and disorders of lipid metabolisim.

1. DENOVO SYNTHESIS OF FATTY ACIDS
AND
DISORDERS OF LIPID METABOLISIM
K.K.WAGH COLLEGE OF PHARMACY,NASHIK
CREATED BY-ROHIT CHAUDHARI

2. CONTENT-
-INTRODUCTION
-FATTY ACID SYNTHESIS STAGES
-DESORDERS OF LIPID METABOLISM
-REFERENCE

3. DENOVO SYNTHESIS OF FATTY ACIDS
The dietary carbohydrates and amino acids, when consumed in excess, can be
converted to fatty acids and stored as triacylglycerols. De novo (new) synthesis
of fatty acids occurs predominantly in liver, kidney, adipose tissue and lactating
mammary glands. The enzyme machinery for fatty acid production is located in
the cytosomal fraction of the cell. Acetyl CoA is the source of carbon atoms
while NADPH provides the reducing equivalents and ATP supplies energy for
fatty acid formation.
INTRODUCTION-

4. FATTY ACID SYNTHESIS STAGES-
THE FATTY ACID SYNTHESIS MAY BE LEARNT IN 3 STAGES
I. PRODUCTION OF ACETYL COA AND NADPH
II. CONVERSION OF ACETYL COA TO MALONYL COA
III. REACTIONS OF FATTY ACID SYNTHASE COMPLEX.

5. I. PRODUCTION OF ACETYL COA AND NADPH
➡ACETYL COA IS PRODUCED IN THE MITOCHONDRIA BY...
➡ OXIDATION OF PYRUVATE
➡ OXIDATION OF FATTY ACIDS
➡ DEGRADATION OF SOME AMINO ACIDS &
➡KETONE BODIES.
➡ HOWEVER, MITOCHONDRIA IS NOT PERMEABLE FOR ACETYL COA.
➡ SO, AN ALTERNATE ARRANGEMENT IS MADE FOR THE TRANSFER OF
ACETYL COA TO CYTOSOL IN THE FORM OF CITRATE.

6. ➡ACETYL COA CONDENSES WITH OXALOACETATE IN MITOCHODRIA TO
FORM CITRATE.
➡CITRATE IS FREE TRANSPOTED TO CYTOSOL.
➡ HERE IT IS CLEAVED BY CITRATE LYASE TO ACETYL COA AND OXALOACETATE.
➡ OXALOACETATE IN THE CYTOSOL IS CONVERTED TO MALATE.
➡ MALATE DEHYDROGENASE CONVERT MALATE TO PYRUVATE WITH PRODUCTION OF NADPH
AND CO₂
➡ TRANSPORT OF ACETYL COA FROM MITOCHONDRIA TO CYTOSOL IS COUPLED WITH
PRODUCTION OF NADPH AND CO₂. BOTH OF THEM ARE UTILIZED FOR FA SYNTHESIS.

8. II.CONVERSION OF ACETYL COA TO MALONYL COA
➡ ACETYL COA IS CARBOXYLATED TO MALONYL COA BY ACETYL COA
CARBOXYLASE.
➡ATP DEPENDENT AND BIOTIN IS REQUIRED FOR CO, FIXATION.
➡ ACETYL COA CARBOXYLASE IS THE REGULATORY ENZYME IN THIS
PATHWAY.

9. FATTY ACID SYNTHASE MULTIENZYME COMPLEX
• IT IS A POLYPEPTIDE CONTAINING SEVEN ENZYME ACTIVITIES & ACYL CARRIER PROTEIN (ACP) UNIT.
• IT IS DIMER COMPOSED OF 2 IDENTICAL MONOMER UNITS.
• EACH MONOMER IS IDENTICAL HAVING ALL 7 ENZYME ACTIVITY OF FATTY ACID SYNTHASE
• ACP-SEGMENT CONTAIN A 4-PHOSPHOPANTETHEINE GR. THIS PROVIDE SULFHYDRYL (-SH)
GROUP TO WHICH THE GROWING FATTY ACID CHAIN IS ATTACHED.
• THUS, THE FUNCTION OF ACP IN FA SYNTHESIS IS ANALOGOUS TO COENZYME A IN FATTY ACID
AXIDATION.
• ONE MORE-SH GROUP IS CONTRIBUTED BY A SPECIFIC CYSTEINE RECIDUE OF 3-KETOACY!
SYNTHASE.
• BOTH-SH GROUPS PARTICIPATE IN FATTY ACID SYNTHESIS.
• 2 FUNCTIONAL SUBUNIT OF FAS INDEPENDENTLY OPERATE & TWO SYNTHESIZE FATTY ACIDS SIMULTANEOUSLY.

11. III.REACTIONS OF FATTY ACID SYNTHASE COMPLEX.
➡ THE 2 "C" FRAGMENT OF ACETYL COA IS TRANSFERRED TO ACP OF FAS, BY THE ENZYME ACETYLTRANACYLASE.
• ACETYL UNIT IS THEN TRANSFERRED TO CYSTEINE-SH OF THE ENZYME
• THUS ACP SITE FALLS VACANT.
➡ THE ENZYME MALONYL TRANSACYLASE TRANSFER MALONATE FROM MALONY! COA TO ACP TO FORM ACETYL-
MALONYL ENZYME.
➡ NOW FATTY ACID SYNTHASE HAS TWO GROUP ATTACHED TO IT.
➡ AN ACETYL GROUP TO CYSTEINE-SH AND MALONYL GROUP AT ACP-SH.
➡ ENZYME COMPLEX IS NOW READY FOR CHAIN ELONGATION PROCESS
➡ IT DONE BY FOLLOWING FOUR STEPS....
→ CONDENSATION
→REDUCTION
→DEHYDRATION AND
→SATURATION

13. •THE CARBON CHAIN ATTACHED TO ACP IS TRANSFERRED TO CYS-SH
• THE REACTION OF 2-6 ARE REPEATED 6 TIMES.
• EACH TIME, THE FATTY ACID IS ELONGATED BY 2 "C" UNIT.
• AT THE END OF 7 CYCLES, A 16 CARBON FATTY ACID (SATURATED) IS FORMED AT ACP.
•THE ENZYME THIOESTERASE SEPARATES PALMITATE FROM FATTY ACID SYNTHASE.
• THIS COMPLETE FATTY ACID SYNTHESIS.

14. DIAGRAMETIC REPRESENTATION

15. DESORDERS OF LIPID METABOLISM
1.HYPERCHOLESTEROLEMIA
HYPERCHOLESTEROLEMIA IS THE TERM USED TO REFER TO A HIGH BLOOD
CHOLESTEROL LEVEL. CHOLESTEROL IS A WAXY SUBSTANCE THAT IS PRODUCED
BY THE LIVER AND IS A COMPONENT OF ALL CELLS FOUND IN THE BODY.
CHOLESTEROL IS REQUIRED FOR VARIOUS BODILY FUNCTIONS INCLUDING THE
SYNTHESIS OF CELL MEMBRANES AND CERTAIN HORMONES AND THE
PRODUCTION OF SUBSTANCES REQUIRED FOR FAT DIGESTION. HOWEVER, A
CHOLESTEROL LEVEL THAT IS TOO HIGH CAN INCREASE THE RISK OF CORONARY
ARTERY DISEASE.

16. HYPERCHOLESTEROLEMIA-
INCREASE IN PLASMA CHOLESTEROL (> 200 MG/DL) CONCENTRATION IS KNOWN AS
HYPERCHOLESTEROLEMIA AND IS OBSERVED IN MANY DISORDERS
1. DIABETES MELLITUS : DUE TO INCREASED CHOLESTEROL SYNTHESIS SINCE THE
AVAILABILITY OF ACETYL COA IS INCREASED.
2. HYPOTHYROIDISM (MYXOEDEMA) : THIS IS BELIEVED TO BE DUE TO DECREASE IN THE
HDL RECEPTORS ON HEPATOCYTES.
3. OBSTRUCTIVE JAUNDICE : DUE TO AN OBSTRUCTION IN THE EXCRETION OF CHOLESTEROL
THROUGH BILE.
4. NEPHROTIC SYNDROME : INCREASE IN PLASMA GLOBULIN CONCENTRATION IS THE
CHARACTERISTIC FEATURE OF NEPHROTIC SYNDROME. CHOLESTEROL ELEVATION IS DUE TO
INCREASE IN PLASMA LIPOPROTEIN FRACTIONS IN THIS DISORDER.
HYPERCHOLESTEROLEMIA IS ASSOCIATED WITH ATHEROSCLEROSIS AND CORONARY HEART
DISEASE (CHD). MORE SPECIFICALLY, LDLCHOLESTEROL IS POSITIVELY CORRELATED,
WHEREAS HDL-CHOLESTEROL IS NEGATIVELY CORRELATED WITH CHD.

17. 2.ATHEROSCLEROSIS
ATHEROSCLEROSIS (GREEK: ATHERE—MUSH) IS A COMPLEX DISEASE CHARACTERIZED BY
THICKENING OR HARDENING OF ARTERIES DUE TO THE ACCUMULATION OF LIPIDS
(PARTICULARLY CHOLESTEROL, FREE, AND ESTERIFIED) COLLAGEN, FIBROUS TISSUE,
PROTEOGLYCANS, CALCIUM DEPOSITS ETC. IN THE INNER ARTERIAL WALL.
ATHEROSCLEROSIS IS A PROGRESSIVE DISORDER THAT NARROWS AND ULTIMATELY BLOCKS
THE ARTERIES. INFARCTION
IS THE TERM USED TO INDICATE THE STOPPAGE OF BLOOD FLOW RESULTING IN THE DEATH
OF AFFECTED TISSUE. CORONARY ARTERIES—THE ARTERIES SUPPLYING BLOOD TO HEART—
ARE THE MOST COMMONLY AFFECTED LEADING TO MYOCARDIAL INFARCTION OR HEART
ATTACKS.

18. CAUSES OF ATHEROSCLEROSIS AND CHD-
THE DEVELOPMENT OF ATHEROSCLEROSIS AND THE RISK FOR THE CORONARY
HEART DISEASE
(CHD) IS DIRECTLY CORRELATED WITH PLASMA CHOLESTEROL AND LDL. ON THE
OTHER
HAND, PLASMA HDL IS INVERSELY CORRELATED WITH CHD.
DISORDERS THAT MAY CAUSE ATHEROSCLEROSIS-
CERTAIN DISEASES ARE ASSOCIATED WITH ATHEROSCLEROSIS. THESE INCLUDE
DIABETES
MELLITUS, HYPERLIPOPROTEINEMIAS,NEPHROTIC SYNDROME, HYPOTHYROIDISM
ETC. MANY
OTHER FACTORS LIKE OBESITY, HIGH CONSUMPTION OF SATURATED FAT,
EXCESSIVE SMOKING,
LACK OF PHYSICAL EXERCISE, HYPERTENSION, STRESS ETC., ARE THE PROBABLE
CAUSES OF
ATHEROSCLEROSIS.

19. SYMPTOMS-

20. FATTY LIVER DISEASE MEANS YOU HAVE EXTRA FAT IN YOUR LIVER.
YOU MIGHT HEAR YOUR DOCTOR CALL IT HEPATIC STEATOSIS.
HEAVY DRINKING MAKES YOU MORE LIKELY TO GET IT. OVER TIME,
TOO MUCH ALCOHOL LEADS TO A BUILDUP OF FAT INSIDE YOUR
LIVER CELLS. THIS MAKES IT HARDER FOR YOUR LIVER TO WORK.
BUT YOU CAN GET FATTY LIVER DISEASE EVEN IF YOU DON’T DRINK
A LOT OF ALCOHOL.
3.FATTY LIVER

22. FATTY LIVER MAY OCCUR DUE TO TWO MAIN CAUSES.
1. INCREASED SYNTHESIS OF TRIACYLGLYCEROLS
2. IMPAIRMENT IN LIPOPROTEIN SYNTHESIS.
1. INCREASED TRIACYLGLYCEROL SYNTHESIS : MOBILIZATION OF FREE FATTY ACIDS
FROM
ADIPOSE TISSUE AND THEIR INFLUX INTO LIVER IS MUCH HIGHER THAN THEIR
UTILIZATION.
THIS LEADS TO THE OVERPRODUCTION OF TRIACYLGLYCEROLS AND THEIR
ACCUMULATION IN
LIVER. DIABETES MELLITUS, STARVATION, ALCOHOLISM AND HIGH FAT DIET ARE
ASSOCIATED WITH INCREASED MOBILIZATION OF FATTY ACIDS THAT OFTEN CAUSE
FATTY
LIVER. ALCOHOL ALSO INHIBITS FATTY ACID OXIDATION AND, THUS, PROMOTES FAT
SYNTHESIS AND ITS DEPOSITION.

23. 2. IMPAIRED SYNTHESIS OF LIPOPROTEINS : THES SYNTHESIS OF VERY
LOW DENSITY
LIPOPROTEINS (VLDL) ACTIVELY TAKES PLACE IN LIVER. VLDL
FORMATION REQUIRES
PHOSPHOLIPIDS AND APOPROTEIN B. FATTY LIVER CAUSED BY
IMPAIRED LIPOPROTEIN
SYNTHESIS MAY BE DUE TO :
• A DEFECT IN PHOSPHOLIPID SYNTHESIS;
• A BLOCK IN APOPROTEIN FORMATION;
• A FAILURE IN THE FORMATION/SECRETION OF LIPOPROTEIN.

24. OBESITY IS A COMPLEX DISEASE INVOLVING AN EXCESSIVE AMOUNT OF BODY FAT.
OBESITY ISN'T JUST A COSMETIC CONCERN. IT IS A MEDICAL PROBLEM THAT
INCREASES YOUR RISK OF OTHER DISEASES AND HEALTH PROBLEMS, SUCH AS
HEART DISEASE, DIABETES, HIGH BLOOD PRESSURE AND CERTAIN CANCERS
4.OBESITY

25. OBESITY
OBESITY IS AN ABNORMAL INCREASE IN THE BODY WEIGHT DUE TO EXCESSIVE FAT
DEPOSITION.
NUTRITIONAL BASIS-
MEN AND WOMEN ARE CONSIDERED AS OBESE IF THEIR WEIGHT DUE TO FAT (IN
ADIPOSE
TISSUE), RESPECTIVELY, EXCEEDS MORE THAN 20% AND 25% OF BODY WEIGHT.
OBESITY
IS BASICALLY A DISORDER OF EXCESS CALORIE INTAKE, IN SIMPLE LANGUAGE—
OVEREATING.
IT HAS TO BE REMEMBERED THAT EVERY 7 CALORIES OF EXCESS CONSUMPTION
LEADS TO 1 G
FAT DEPOSIT AND INCREASE IN BODY WEIGHT. OVEREATING—COUPLED WITH
LACK OF PHYSICAL EXERCISE—CONTRIBUTE TO OBESITY.

26. OBESITY DUE TO VIRUS INFECTION-
IT WAS FOUND THAT AROUND 15% OF PEOPLE WEIGHING
MORE THAN 120 KG HAD
ANTIBODIES TO ADENOVIRUS-36 IN THEIR BLOOD, IMPLYING
THAT THIS VIRUS INFECTION
(CAUSES COLD, DIARRHEA ETC.), BY AN UNKNOWN
MECHANISM CONTRIBUTES TO OBESITY.
SURPRISINGLY, ADENOVIRUS-36 INFECTED INDIVIDUALS HAVE
NORMAL SERUM CHOLESTEROL
AND OTHER LIPID PARAMETERS.

27. 5.DISORDERS OF PLASMA LIPOPROTEINS-
INHERITED DISORDERS OF LIPOPROTEINS ARE
ENCOUNTERED IN SOME INDIVIDUALS RESULTING
IN PRIMARY HYPER-OR HYPOLIPOPROTEINEMIAS.
THESE ARE DUE TO GENETIC DEFECTS IN
LIPOPROTEIN METABOLISM AND TRANSPORT

28. HYPERLIPOPROTEINEMIAS
ELEVATION IN ONE OR MORE OF THE LIPOPROTEIN FRACTIONS
CONSTITUTES HYPERLIPOPROTEINEMIAS .
THESE DISORDERS MAY BE EITHER PRIMARY OR SECONDARY.
HYPOLIPOPROTEINEMIAS
ALTHOUGH LOW LEVELS OF PLASMA LIPIDS (NOT HDL!) WITHIN THE
NORMAL RANGE MAY BE BENEFICIAL TO THE BODY, VERY LOW LIPID
LEVELS ARE UNDESIRABLE. THESE ARE COMMONLY ASSOCIATED WITH
CERTAIN ABNORMALITIES.THERE ARE TWO TYPES-
1. FAMILIAL HYPOBETALIPOPROTEINEMIA
2. ABETALIPOPROTEINEMIA

29. 6.CHOLELITHIASIS -
BILE SALTS AND PHOSPHOLIPIDS ARE RESPONSIBLE FOR
KEEPING THE CHOLESTEROL IN BILE IN A SOLUBLE STATE. DUE
TO THEIR DEFICIENCY (PARTICULARLY BILE SALTS), CHOLESTEROL
CRYSTALS PRECIPITATE IN THE GALL BLADDER OFTEN RESULTING
IN CHOLELITHIASIS —CHOLESTEROL GALL STONE DISEASE.

30. REFFERENCE-
-WWW.WIKIPEDIA.ORG
-WWW.GOOGLE.COM
-BIOCHEMISTRY BOOK BY U.SATYANARAYANA AND
U.CHAKRAPANI
- BIOCHEMISTRY BOOK BY DAVID L. NELSON MICHAEL M. COX-
LEHNINGER.
-GUIDANCE OF SUBJECT TEACHER

31. THANK YOU