01:694:301 Lecture Notes - Lecture 16: Malate Dehydrogenase, Pyruvate Carboxylase, Acetyl-Coa
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14 Nov 2018
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Chapter 16 – ‘Glycolysis and Gluconeogenesis’ PART II
• First, notice that all of the structures in Fig. 16.24 are exactly the same as the structures in
16.2 except for oxaloacetate (OAA), which is new
o Then notice that the enzymes shown in blue are all the same.
o The red enzymes replace the irreversible steps in Fig. 16.2
• SO in a real way, despite what every textbook says,
gluconeogenesis can b thought of as a
reversal of glycolysis, with some useful changes
o Understanding this makes the pathway much easier to learn, especially if you already
know glycolysis
• Gluconeogenesis is the synthesis of glucose from noncarbohydrate precursors; helps
maintain level of glucose in blood so brain and muscle can use to satisfy metabolic demand
o The gluconeogenic pathway converts pyruvate (PYR) to glucose
o Noncarb precursors are converted to PYR or enter pathway as intermediates (OAA and
DHAP)
! Majority of precursors " aa, lactate, glycerol
• Lactate converted to PYR by lactate DH
• AA derives from breakdown proteins
• Glycerol/fatty acid produced by hydrolysis of triacylglycerols
o Animals cannot convert fatty acids to glucose
o Glycerol enters pathway as DHAP
o Major site is in the liver (minor kidney)
• The THREE irreversible steps in glycolysis are bypassed in gluconeogenesis in new steps:
o 1)
PEP is formed from pyruvate by way of OAA
o 2)
Fructose 6- phosphate is formed from F-1,6-BP by hydrolysis of phosphate
ester at C-1
o 3)
Glucose is formed by hydrolysis of glucose-6-phosphate
• Making phosphoenolpyruvate (PEP) is difficult, and in eukaryotic cells requires a visit
to the mitochondrial matrix
o Pyruvate carboxylase uses biotin, ATP, and activating acetyl CoA to form OAA
! Biotin is covalently attached prosthetic group which serves as carrier of O2;
attached to pyr carboxylase by long, flexible chain
• Biotin is not carboxylated unless Acetyl CoA is bound to enzyme
o OAA converted to malate and moves back to cytoplasm, where it is re-oxidized to OAA
! OAA reduced malate inside mitochondria by
NADH-linked malate dehydrogenase
! After malate is back in cytoplasm, it gets oxidized to OAA by
NAD+-linked malate DH
! Also provides NADH for future use
o OAA simultaneously gets decarboxylated and phosphorylated by PEPCJ " PEP
! Phosphoryl donor is GTP
! Both carboxylation and decarboxylation are used to form PEP because…
Biotin