Biochemistry Lec PDF

BIOCHEMISTRY LEC LIPID METABOLISM Digestion of Lipids Starts in STOMACH with the aid of: LINGUAL LIPASE - acid stable Degradation of Cholesterol Esters - primary target: short/medium chain Enzyme: CHOLESTEROL ESTERASE fatty acids (milk...

BIOCHEMISTRY LEC LIPID METABOLISM Digestion of Lipids Starts in STOMACH with the aid of: LINGUAL LIPASE - acid stable Degradation of Cholesterol Esters - primary target: short/medium chain Enzyme: CHOLESTEROL ESTERASE fatty acids (milk fat) Cholesterol ester hydrolase breaks down GASTRIC LIPASE cholesterol esters to form cholesterol and fatty - acid stable acids - primary target: long chain fatty Activity is increased in presence of bile salts acids Both enzymes have optimum pH of 4 to 6 Lipids undergo EMULSIFICATION in the SMALL INTESTINES (Duodenum) Emulsification increases surface area of hydrophoic fat droplets so digestive enzymes can act effectively Degradation of Phospholipids Done by: Enzyme: PHOSPHOLIPASE A2 - PERISTALSIS (Proenzyme) - mechanical mixing Activator. : TRYPSIN (requires bile salts for - BILE SALTS activity) - has detergent properties Removes one fatty acid from carbon 2 of a phospholipid Degradation of Dietary Lipids Pancreatic enzymes degrade - Triglycerides (formation of lipoproteins) - Cholesterol esters (bonding — cholesterol & other fats) - Phospholipids (— cellular membrane; Enzyme: LYSOPHOSPHOLIPASE structure of cells) Removes fatty acid at Carbon 1 to form glycerolphosphorylbase Enzymes that Aid in Lipid Digestion Degradation of Triglycerides Enzyme: PANCREATIC LIPASE Lipase remove fatty acids to Carbon 1 & 3 of the Triglyceride to form 2-monoacylglycerol and free fatty acids  Micelles Control of Lipid Digestion - Soluble in aqueous intestinal environment CHOLECYSTOKININ - Absorbed at the brush border of Site of Release: released in blood from enterocytes jejunum and lower duodenum in response to lipids and partially digested proteins entering the small intestines Actions: - Gallbladder - contraction and release of bile - Pancreatic exocrine cells - release of digestive enzymes - Decreases gastric motility Resynthesis of TAG and Cholesterol esters SECRETIN Site of Release: released in blood from other Absorbed lipids move to endoplasmic intestinal cells in response to low pH of chyme reticulum (partially digested food) Long Chain fatty acid -> converted to fatty Actions: acyl coA by fatty acyl CoA synthase - Release of a watery solution by 2- monoacylglycerol use fatty acyl coA to pancreas and liver revert into TAG by Triglyceride Synthase - High in carbonate — appropriate pH (Acyltransferase) for action of pancreatic enzymes Lipid Absorption Absorption of Lipids Lipids are absorbed in MUCOSAL CELLS of SMALL INTESTINE (jejunum) Jejunum gets: - Free fatty acids Note: - Free cholesterol Triglycerides cannot be absorbed directly by - 2-monoacylglycerol body as it passes down in stomach, and stomach Combined with: gastric juices will breakdown triglyceride, - Bile however, our body also need triglycerides - Fat soluble vitamins To form MICELLES Diseases in Lipid Metabolism Lipid Malabsorption STEATORRHEA increased lipid and fat soluble vitamin excretion in feces Caused by defects in:  - Lipid digestion 1. Chylomicrons - Lipid absorption 2. Very Low Density Lipoproteins Presence of fat droplets in stool (VLDL) Characteristic of Stool 3. Intermediate Density Lipoproteins - Bulky (IDL) - Difficult to flush 4. Low Density Lipoproteins (LDL) - Pale and oily appearance 5. High Density Lipoproteins (HDL) - Foul-smelling sometimes — it is not totally formed stool, rather, watery / liquid and/or oil Secretion of Lipids from Enterocytes CHYLOMICRON - formed in ER of enterocytes Chylomicrons - aggregates of Largest lipoprotein (180 to 500 nm in TAG and diameter) cholesterol esters Synthesized in ER of enterocytes - acts as transport Apo 8-48 — main protein component protein Delivers TAG from intestine to tissues After a lipid-rich meal, - Muscle for energy lymph is called CHYLE - Adipose for storage From lymph, Chylomicrons finally enter blood Present in blood after feeding Transport of Forms of Lipids Very Low Density Lipoprotein (VLDL) Formed in the liver TAG, CHOLESTEROL, Cholesterol ester Contain 50% TAGs and 22% Cholesterol - insoluble in water and cannot be Two lipoproteins: Apo 8-100 and Apo-E transported in blood or lymph as free Main transport form of TAG synthesized in molecules liver They assemble with phospholipids and Deliver TAG from liver to peripheral tissue apolipoproteins to form LIPOPROTEINS structure: Low Density Lipoprotein - Hydrophobic core - TAG, Formed in the blood from IDL (Intermediate Cholesterol esters Density Lipoprotein) and liver from IDL - Hydrophilic surfaces - Cholesterol, (enzyme: Liver LIPASE) Phospholipids, Apolipoproteins Enriched in cholesterol and cholesterol esters (50%) Protein component: ApoB-100 Major carrier of Cholesterol to peripheral tissue Cells of all organs have LDL receptors Main Classes of Lipoproteins High Density Lipoproteins  Formed in the liver and partially in small Acetyl CoA intestine - The Center of Lipid Metabolism Contain the great amount of protein (40%) Precursors of Acetyl CoA: Pick up the cholesterol from peripheral tissue, - fatty acids chylomicrons and VLDL - Glucose (through pyruvate) - amino acids - ketone bodies Products of Acetyl CoA Metabolism: Structure of Acetyl CoA Acetyl CoA consist of two part: - Acetyl group - Coenzyme A Pantothenic acid (not synthesized in man — an essential nutrient) Fatty Acid Synthesis Occurs in the: Significance of Fatty Acid Metabolism liver Fatty acids are taken up by cells, where they adipose tissue (fat) may serve as: Lactating mammary glands - precursors in the synthesis of other compounds starts after a meal rich in carbohydrates - fuel for energy production - substrate for ketone body synthesis Ketone Bodies can be used by Skeletal muscles, cardiac muscle, renal cortex and brain to get energy Ketone bodies have been used as markers of hepatic energy metabolism  Ketones can be caused by a lack of adequate Causes of Raised Levels of Ketone Bodies food intake Fuel metabolism in starvation. After several 1. Starvation -> no carbohydrate weeks of starvation, ketone bodies become the reserves Mobilization of FFA and major fuel of the brain their oxidation to get energy -> Exceeds liver capacity to oxidize Synthesis of Ketone Bodies acetyl CoA -> Ketogenesis synthesized from acetyl CoA 2. Uncontrolled insulin dependent Ketone body synthesis from acetyl CoA diabetes mellitus occurs in hepatic mitochondria 3. High fat intake 4. Strenuous exercise Regulation of Ketogenesis Ketone body production is regulated primarily Regulation of Cholesterol Synthesis by availability of acetyl CoA Cholesterol synthesis has to be tightly If mobilization of fatty acids from adipose regulated as the imbalance between tissue is high, hepatic beta-oxidation will occur synthesis/intake and utilization leads to at a high rate, and so will synthesis of ketone accumulation of cholesterol in blood vessels bodies from the resulting acetyl CoA which have serious consequences — The rate of ketone body production increases atherosclerosis in starvation HMGCoA reductase is the rate limiting enzyme and it is the major control point for Normal Levels of Ketone Bodies cholesterol synthesis In blood of a well fed individual -> less than 3 mg /dL Fate of Cholesterol In urine -> less than 125 mg in 24 hrs Conversion to bile acids and bile salts which are then excreted in feces Terminologies Secreted in bile, taken to intestines and then excreted Conversion to neutral sterols by bacteria in intestines and then excreted Synthesis of Vitamin D Synthesis of steroid hormones Normal Levels of Blood Cholesterol In adults, normal level is: 150-200 mg/dL Risk of developing cardiovascular diseases increases when the level is above 200 mg/dL PROTEIN METABOLISM Digestion of Proteins Start in STOMACH - acidic environment helps digest proteins Ends in SMALL INTESTINES PEPSIN begins the process of protein digestion by cleaving specific amide linkages to form a variety of smaller peptides Smaller peptides promote release of hormones and enzymes by pancreas and small intestines such as: Digestion and Absorption Absorption of Proteins  Amino acids that generate precursors of glucose (Pyruvate or citric acid cycle intermediates — GLUCOGENIC. Amino acids that are degraded to Acetyl CoA or Protein Digestion and Absorption Process Acetoacetyl CoA — KETOGENIC — give rise to ketone bodies Some amino acids are BOTH Disease of Protein Metabolism Aminoacidopathies Rare inherited disorders of amino acid metabolism Exist either as abnormality of specific enzyme in metabolic pathway OR in membrane transport system for amino acids Phenylketonuria (PKU) Autosomal recessive trait Rare; 1 to 10,000 births Several variants of this disease Classic PKU — Phenylalanine hydroxylase Tyrosenemia I — FAA Hydrolase Tyrosenemia II — Tyrosine aminotransferase Alkaptonuria — Homogentisate oxidase Tyrosinemia Familial metabolic disorder of tyrosine catabolism Rare; 1 to 10.000 Presence of tyrosine crystals in urine Tyrosenemia I — FAA Hydrolase Metabolism of Proteins Tyrosenemia II — Tyrosine aminotransferase Elevated tyrosine damage liver; fatal to infants, cirrhosis to adults Alkaptonuria Maple Syrup Urine Disease (MSUD) Blood Protein Tests Isovaleric Acidemia Blood Non-protein nitrogen compounds tests Homocystinuria An immediate amino acids in the synthesis of cysteine from methionine Impaired activity of cystathionine ß-synthase Enzyme requires vitamin B6 as cofactor Rare; 1 in 200,000 births Cystinuria Defect in amino acid transport system rather than a metabolic enzymes deficiency Cystine is insoluble, when high levels in urine, tends to precipitate in kidney tubules and form renal calculi