Lipogenesis
Lipogenesis
Lipogenesis
Formerly considered
Now
extramitochondrial system Responsible for complete synthesis of Palmitate from Acetyl-CoA in the Cystosol
Glucose
Most mammals Primary substrate for lipogenesis Ruminants (Mammals with four-chambered stomachs and two-toed foot) Main fuel molecule produced by the diet Primary substrate
Acetate
1.
Production of Acetyl-CoA and NADPH Biosynthesis of Malonyl-CoA Reactions of Fatty Acid Synthase Complex
2.
3.
Sources of NADPH:
Pentose Phosphate Pathway
Main source Its oxidative reactions are the chief source of the hydrogen required for the reductive synthesis of fatty acids.
Malate enzyme
NADP Enzyme dehydrogenase Enzyme in the conversion of malate to pyruvate
Isocitrate dehydrogenase
Probably not a substantial source.
Source of the 2 carbon sub-units added to the growing FA chain on FA synthase complex Requirements:
Bicarbonate (for the initial reaction for the carboxylation of Acetyl-CoA to Malonyl-CoA) ATP Enzyme: Acetyl-CoA Carboxylase
3 Components of Acetyl-CoA carboxylase:
1.Biotin carboxylase 2.Biotin carboxylase carrier protein 3.Transcarboxylase Co-enzyme: Biotin (the enzyme prosthetic group)
O CH3- C S-CoA
-OOC-CH 2
C S-CoA
Acetyl-CoA
Enz-BiotinEnz-Biotin- *COO *COO-
Malonyl-CoA
Enz- Biotin
ADP + Pi
A polypeptide containing seven enzyme activities. A dimer of two identical polypeptide monomers, 1 and 2, each consisting of: Seven enzyme activities:
a) b) c) d) e) f) g) Ketoacyl synthase Acetyl transacylase Malonyl transacylase Hydratase Enoyl reductase Ketoacyl reductase Thioesterase
~S CoA
HSPan
1 CysHS
ACETYL TRANSACYLASE
HSCys
2 PanHS
HS CoA
CysS
O CCH3
2 PanS
1 CysHS
HOOCCH2C
HSCys
S CoA
2 PanHS
HS CoA
CysS ~
2 PanS ~
O
1
CysS
CCH3 CCH2COOH
2 PanS
O
3-ketoacyl synthase CO2
1
CysSH
2 PanS
CCH2 CCH3 O
CysSH
O 2 PanS CCH2CCH3 O
NADPH
NADP+
1
CysSH
OH
2 PanS CCH2 CHCH3 O -hydroxyacyl enzyme
CysSH
Enzyme: Hydratase
OH CCH2COOH CHCH3 -hydroxyacyl enzyme
2 PanS
O
H2O
1
Hydratase
CysSH
2 PanS
CysSH
2 PanS
CCH CHCH3
O
NADPH
Enoyl Reductase
NADP+
1
CysSH
2 PanS
Repeated 6 more times New malonyl residue being incorporated during each sequence until a saturated 16-carbon acyl radical (palmityl) has been assembled. Enzyme: Thioesterase (deacylase)
CH2CO S CoA + 7HOOCCH2CO S CoA + 14NADPH + 14H+ CH3(CH2)14COOH +7CO2 + 6H2O + 8CoA SH + 14NADP+
Two centers of activity in one dimer complex that function independently and simultaneously.