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BIOCHEM-Lipid_Metabolism_2

BIOCHEM-Lipid_Metabolism_2

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10/01/2013

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TRIACYLGLYCEROLSBIOSYNTHESIS AND METABOLISM
..in animals synthesized in liver and intestines. They are stored in different cells as lipid droplets, fat globules, lipidparticles etc. usually they are enclosed by hydrophobicphospholipids and hydrophobic molecules called perilipins.
Biosynthesis of TriacylglycerolsTwo Main Biosynthetic Pathways•sn-glycerol-3-phosphate pathway-predominates in liver and adipose tissue-Kennedy pathway•monoacylglycerol pathway-predominates in intestines•acyl-CoA independent transacylationsn-Glycerol-3-Phosphate Pathway
α
-glycerophosphatepathway•Kennedy pathway•sn-glycerol-3-phosphate/alpha glycerophosphate pathway-main source of the glycerolbackbone-produced by the catabolism of glucose (glycolysis)-produced by the action of glycerol kinaseon freeglycerol, to a lesser extent•de novo pathway-glyceroneogenesisvia pyruvate-the main source in adipose tissue
..glycerol3 phosphate is the main source of the glycerolbackbone. Glycerol is produced through glycolysis. Initially its phophorylated to form glycerol 3 phosphate through glycerol-3-kinase. Majority of glycerol is synthesized denovo. Using fatty acid acyl with the help of glycerol 3phosphate acyl transferase, lisophosphatidic acid is formed.The acyl group is attached to C1. With another activatedacyl group, and with the help of acyl glycerophosphate acyltransferase enzyme, phosphatidic acid is formed. Then by means of phosphatidic acid phosphohydrolase or PAP,diacylglycerol is formed. Again there will be acylation,finally forming triacylglycerol.
Phosphatidic Acid Phosphohydrolase• removes phosphate group of phosphatidic acid•PAP or ‘phosphatidate phosphatase’ or ‘lipid phosphatephosphatase• also important as it produces diacylglycerols as essentialintermediates in the biosynthesis of phosphatidylcholineand phosphatidylethanolamine•in mammals, much of the phosphatase activity leading to triacylglycerol biosynthesis resides in three relatedcytoplasmic proteins, termed lipin-1, lipin-2, and lipin-3
Lipins
•much of the phosphatase activity leading to triacylglycerolbiosynthesis resides•three related cytoplasmic proteins, termed lipin-1, lipin-2,and lipin-3•are tissue specific meaning each have distinctiveexpression and function
Lipin-1
SUBJECT: BIOCHEMISTRYTOPIC:LIPID METABOLISM 2
(PHOSPOLIPIDSAND SHINGOLIPIDS)
 LECTURER: DR. LAYGODATE: NOV. 2010
 
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•PAP1
accounts for all the PAP activity in adipose tissueand skeletal muscle
occurs mainly in the cytosoliccompartment of cells
 translocatedto the endoplasmic reticulum inresponse to elevated levels of fatty acids withincells
(remember synthesis regulation..cAMP and fatty acidbound to the membrane of ER. It would stimulate synthesisof triacylglycerol..)
activity requires Mg2+ions
inhibited by N-ethylmaleimide
(also in electron transport chain..inner mitochondrial membrane but molecules can cross..for ATP  synthesis, ATP synthase is the enzyme at complex 5 beta subunit of F1 component. Now we know that ADP is mostly found in the cytosol because they are transported out of the mitochondrion where they are needed. ATP enters themitochondria in exchange for ADP through Adenosinenucleoside translocase.For inorganic phosphate, nitroxyl ions is exchanged to takephosphate into the mitochondrial matrix using theinorganic phosphate hydroxyl antiporter or translocase.Incidentally, NEM inhibits this translocase together withlipin 1.)
membrane-bound activity responsible forsynthesisingdiacylglycerolsas aphospholipidintermediate is independent of Mg2+concentration and is not sensitive to theinhibitor
has a dual role:
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it operates in collaboration with known nuclearreceptors as a
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 transcriptional coactivatorto modulate lipidmetabolism
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expression of genes involved in lipidmetabolism
 
abnormalities in lipin-1 expression are known to beinvolved in human disease states that may lead to the metabolic X syndrome (
person is obese,hypertension, diabetes, abdominal obesity, pear  shaped or apple shaped figure where waistcircumference greater than 40)
 
Lipin-2
a similar phosphatidate phosphohydrolase
present mainly in liver
regulated dynamically by fasting and obesity(in mice)
DiacylglycerolAcyltransferase(DGAT)
acylates resultant 1,2-diacyl-sn-glycerol to form the triacyl-sn-glycerol
dedicated triacylglycerol-forming enzyme
 target for pharmaceutical intervention in obesityand attendant ailments•two DGAT enzymes:-DGAT 1 & DGAT 2-structurally & functionally distinct
DGAT1
expressed in skeletal muscle, skin and intestine
lower levels of expression in liver and adipose tissue
important modulators of energy metabolism
 the only one present in the epithelial cells thatsynthesize milk fat in the mammary gland
DGAT2
 the main form of the enzyme in hepatocytes andadipocytes
 though it is expressed much more widely in tissues
important modulators of energy metabolism
especially important in controlling the homeostasisof triacylglycerols in vivoDihydroxyacetone phosphate in the peroxisomes or plasmareticulum can be acylated, can be used as a substrate for the addition of the activated acyl group to form 1-acyldihydroxyacetone phosphate which is subsequentlyreduced to lysophosphatidic acid. This is part of plasmalogen biosynthetic pathway (PAFs)
Utilizes 2-MAG, (w/free fatty acids..short and medium chainare brought to liver for beta oxidation..long chain will formtriacylglycerol resynthesis after which it will be coated with
 
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apolipoprotein b48 to form chylomicrons. Chylomicrons willtransport these lipids in the lymphatic system and bebrought back through the thoracic duct which will empty tosubclavian vein.)
Third Biosynthetic Pathway
..less well known...Wherein there is diacylglycerol transacylase enzyme usingdiacylglycerol, so that they will condense to formtriacylglycerols plus monoacylglycerols.
Acyl-CoAIndependent Transacylation
 third biosynthetic pathway
less well known
synthesize TAGs by an acyl-CoAindependent transacylation
uses two racemicdiacylglycerols
first detected in intestinal microvillus cells
catalysedby a diacylglyceroltransacylase
 two diacylglycerolenantiomersparticipate in thereaction
 there is equal facility to transfer a fatty acylgroup
production of triacylglycerolsand a 2-monoacyl-sn-glycerol
similar reaction has been observed in seed oils
PHOSPHOLIPIDS
What is a phospholipid?
Amphiphatic moleculesHas glycerol 3-phosphate backboneCarbons 1 and 2 of glycerol acylated:C1 substituent – saturated fatty acidC2 substituent – unsaturated fatty acidClassified according to substituent on PO4 groupMajor phospholipids in animals: phosphatidylcholine,phosphatidylethanolamine & sphingomyelin (myelin sheath)
..on the third carbon, a phosphate group is usually attached with a nitrogenous base or amino acid,determining the specific phospholipid..in other words, whatmakes one phospholipid different from another is the group attached to the phosphate group on the third carbon(c3).
BIOSYNTHESIS
Occurs at surface of endoplasmic reticulum and innermitochondrial membrane..organ primarily the liverPhosphatidic acid is the central biosyntheticintermediateRequires nucleotide cytidine triphosphate (CTP)...base cytidine; sugar - ribosein
the next table:...to synthesize phophatidic acid, glycolysis is the pathway concerned with the oxidation of glucose. There are twothings that come out of it:dihydroxyacetone phosphate glycerol (*glycerol can result from the breakdown of triacylglycerol in adipose tissue)(these are intermediates)..so let’s look at glycerol. It will be phosphorylated by means of glycerol kinase(found only in the liver) with ATP as the source of the phosphate forming glycerol 3phosphate. (3 because the phosphate group is attached atcarbon 3.)...on the other hand, for dihydroxyacetone, it is alsoconverted to glycerol 3 phosphate. The double bonded Oon carbon 2 has to be reduced(introduction of H) to betransformed. Thus the enzyme is glycerol 3-phosphatedehydrogenase with the help of NADH.

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