Lipid Synthesis

1
Lipid Synthesis

• Biochemistry - April 6, 2005
• Chapter 21

Ergosterol!!
2
Other Fatty Acids

• Other fatty acids are derived from Palmitate
• Because mammals do not have the desaturases
  necessary to produce linoleate and a-linolenate,
  these are essential fatty acids, must be present
  in diet

3
Unsaturated Fatty Acids

• Double bonds introduced by mixed-function
  oxidases
• O2 used as an oxidant, accepts 2 electrons from
  FA carbons being oxidized, 2 electrons from NADPH

4
Eicosanoids (20C)

• Arachidonate ? prostaglandin H2 (PGH2) catalyzed
  by cyclooxygenase (COX)
• PGH2 is a precursor for other prostaglandins
  (inflammation) and thromboxanes (clotting)
• Lipoxygenases (cytochrome P450 enzymes) add
  both oxygen atoms to arachidonate to
  synthesize leukotrienes (allergies,
  hypersensitiveresponse).

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Cytochrome P-450 enzymes

• P-450 enzymes contain heme, use O2 as a
  substrate, can bind CO, resulting in maximum
  absorbance at 450 nm.
• Hundreds of family members, involved in
  detoxifying many toxins, drugs (adds hydroxyl to
  increase solubility, excretion)
• Monooxygenases 1 O added to substrate, 1 forms
  H2O
• Dioxygenases both oxygen atoms added to
  substrate

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Triacylglycerols

• Glycerol phosphate synthesized 2 ways in
  adipose tissue, DHAP produced by partial
  gluconeogenesis pathway - glyceroneogenesis
• 2 acyl groups transferred from CoA
• Phosphatidic acid isa precursor for
  phospholipids and triglycerides

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Fat cycling

• Top fatty acids released by adipose tissue,
  excess FAs esterified into triglycerides by
  liver, sent back to adipose.
• Middle glucocorticoids (cortisol) increase
  triglyceride synthesis in liver, decrease it in
  adipose (via effect on PEP carboxykinase
  expression)
• High level of fatty acids in blood, interferes
  with glucose metabolism Type 2 diabetes
  insulin insensitivity
• Bottom thiazolidine-dione drugs have effect
  opposite of glucocorticoids

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Phospholipid synthesis

• Phospholipids synthesized by linking either
  diacylglycerol (DAG) or polar head group to CDP
• 1 phosphate remains, CMP is leaving group (NAS)

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Isoprenoid Synthesis

• Isoprenoids are lipids built from 5C isoprene
  unit -includes sterols, lipophilic hormones,
  hydrocarbon tail of quinones, chlorophyll
• 3 acetyl-CoA ? mevalonate (6C) ? isopentenyl
  pyrophosphate (IPP)(5C) CO2

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IPP Synthesis

• HMG-CoA reductase is key regulated step,
  mevalonate is committed to isoprenoid biosynthesis

• Stimulated by insulin
• Inhibited by glucagon, cholesterol lowering drugs

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Isoprenoid Synthesis

• DMAP IPP ? GPP (10C)
• GPP -cyclase? terpenes
• GPP IPP ? FPP (15C)
• FPP cyclase? sesquiterpenes
• FPP IPP ? Geranylgeranyl pyrophosphate (GGPP)
  (20C)
• GGPP -cyclase? diterpenes
• FPP FPP ? squalene (30C)
• Squalene ? -cyclase? sterols

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Sterols

• Different eukaryotes make different sterols
• Sigmasterol plants
• Ergosterol fungi
• Cholesterol animals synthesized primarily in
  the liver

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Lipoproteins

• Lipids are transported through blood is
  association with lipoproteins.
• Chylomicrons intestine ? tissues
• Remnants taken up and processed by liver
• VLDL Liver ? adipose, muscle
• Removal of triglycerides from VLDL ? LDL (rich in
  cholesterol)
• HDL transportscholesterol to liverfor removal

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Liver Cholesterol

• Lipoproteins taken up by receptor-mediated
  endocytosis
• Cholesterol level in liver determines whether
  more will be produced
• Defect in LDL receptor prevents uptake, leads to
  continual synthesis of cholesterol, accumulates
  to high levels.
• Optimal lipid profile
• Total cholesterol lt200 mg/dL
• HDL gt60 mg/dL
• LDL lt100 mg/dL
• Triglycerides lt150 mg/dL