Biosynthesis of Fatty Acids

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Biosynthesis of Fatty Acids

• Medical Biochemistry
• Lecture 46

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FattyAcids

• Fatty acids are a class of compounds containing
  a long hydrocarbon chain and a terminal
  carboxylate group.
• Nomenculature
• - Systematic name for a fatty acid is derived
  from the name of its parent hydrocarbon by the
  substitution of oic for the final e.
• - For example, the C18 saturated fatty acid
  is called octadecanoic acid (180) because the
  parent hydrocarbon is octadecane.

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F.A. Nomenclature (cont.)

• - C18 with one double bond is called octadecenoic
  acid (181) with two double bonds is called
  octadecadienoic acid (182) with three double
  bonds, octadecatrienoic acid (183).

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Fatty acids vary in chain length and degree of
unsaturation

•  
• Usually contain an even number of carbon atoms,
  typically between 14 and 24. The 16- and
  18-carbon fatty acids are most common.
•  
• May contain one or more double bonds. The double
  bonds in polyunsaturated fatty acids are
  separated by at least one methylene group.
•  
• The configuration of the double bonds in most
  unsaturated fatty acids is cis.

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Properties of fatty acids are markedly dependent
on their chain length and on the degree of
saturation.

• -Melting point of stearic acid is 69.6oC, whereas
  that of oleic acid (with one double bond) is
  13.4oC.
•  
• Melting temperature of palmitic acid (C16) is
  6.5 degrees lower than that of stearic acid (C16)

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FATTY ACID SYNTHESIS (LIPOGENESIS)

• Glucose provides the primary substrate for
  lipogenesis 
• In humans, adipose tissue may not be an important
  site, and liver has only low activity 
• Variations in fatty acid synthesis between
  individuals may have a bearing on the nature and
  extent of obesity, and one of the lesions in type
  I, insulin-dependent diabetes mellitus is
  inhibition of lipogenesis
•  
• DE NOVO SYNTHESIS OCCURS IN CYTOSOL 
• Liver, kidney, brain, lung, mammary gland, and
  adipose tissue.

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Step 1 Formation of Malonylcoenzyme A is the
committed step in fatty acid synthesis It takes
place in two steps carboxylation of biotin
(involving ATP) and transfer of the carboxyl to
acetyl-CoA to form malonyl-CoA.
Reaction is catalyzed by acetyl-CoA carboxylase.
It is a multienzyme protein. The enzyme contains
a variable number of identical subunits, each
containing biotin, biotin carboxylase, biotin
carboxyl carrier protein, and transcarboxylase,
as well as a regulatory allosteric site.
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Step 2

• Fatty acid synthase catalyzes the remaining
  steps. It is a multienzyme polypeptide complex
  that contains acyl carrier protein (ACP). ACP
  contains the vitamin pantothenic acid in the form
  of 4'-phosphopantetheine. ACP takes over the
  role of CoA. 
• It offers great efficiency and freedom from
  interference by competing reactions 
• Synthesis of all enzymes in the complex is
  coordinated, since it is encoded by a single
  gene 
• It is a dimer, and each monomer is identical,
  consisting of one chain containing all seven
  enzyme activities of fatty acid synthase and an
  ACP with a 4'-phosphopantetheine-SH group. Dimer
  is arranged in a "head to tail" configuration.
  Monomer is not active.

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Step 3 Elongation of fatty acid chains occurs
in endoplasmic reticulum

• This pathways "microsomal system" converts fatty
  acyl-CoA to an acyl-CoA derivative having two
  carbons more, using malonyl-CoA as acetyl donor
  and NADPH as reductant catalyzed by the
  microsomal fatty acid elongase system of enzymes.

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Nutritional state regulates lipogenesis

• Lipogenesis converts surplus glucose and
  intermediates such as pyruvate, lactate, and
  acetyl-CoA to fat. 
• Rate is higher in well-fed animals whose diets
  contains a high proportions of carbohydrates. 
• It is depressed under conditions of restricted
  caloric intake, on a high-fate diet, or when
  there is a deficiency of insulin, as in diabetes
  mellitus. All these conditions are associated
  with increased concentrations of plasma free
  fatty acids. 
• There is an inverse relationship between hepatic
  lipogenesis and the concentration of serum-free
  fatty acids. The greatest inhibition of
  lipogenesis occurs over the range of free fatty
  acids (0.3-0.8 µmol/mL pf plasma).

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• Fat in the diet also causes depression of
  lipogenesis in the liver, and when there is more
  than 10 of fat in the diet, there is little
  conversion of dietary carbohydrates to fat.

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SHORT AND LONG-TERM MECHANISMS REGULATE
LIPOGENESIS

• In the short-term, synthesis is controlled by
  allosteric and covalent modification of enzymes
  For long-term, there are changes in gene
  expression
• Short-term
• Acetyl-CoA carboxylase is most important in
  regulating synthesis 
• Activated by citrate, which increases in well-fed
  state and is an indicator of a plentiful supply
  of acetyl-CoA 
• Inhibited by long-chain acyl-CoA.  
• Pyruvate dehydrogenase regulates availability of
  free acetyl-CoA for lipogenesis. Acetyl-CoA
  causes an inhibition of pyruvate dehyrogenase.

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• Hormones (short term)
• Insulin stimulates lipogenesis by several
  mechanisms
• a. increases transport of glucose into the cell
  (e.g., adipose tissues) and thereby increases the
  availability of both pyruvate for fatty acid
  synthesis and glycerol-3-phosphate for
  esterification of the newly formed fatty acids. 
• b. Converts inactive form of pyruvate
  dehydrogenase to the active form in adipose
  tissues 
• c. Activates acetyl-CoA carboxylase 
• d. Insulin depress intracellular cAMP levels,
  inhibits lipolysis 
• e. Insulin antagonizes the actions of glucagon
  and epinephrine

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Long-term

• Expression is increased in response to fed state
  and is decreased in fasting, feeding of fat, and
  in diabetes (adaptive mechanism).