Humboldt State University ® Department of Chemistry

Richard A. Paselk

Chem 438 - Introductory Biochemistry - Spring 2013

Lecture Notes:

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Kreb's TCA Cycle, cont.

Note that because all catalysts (oxaloacetate, enzymes etc.) must be regenerated in looking at the overall operation of the cycle, only the acetyl group of acetyl-CoA can be oxidized completely.

Integrated Regulation of Aerobic Glucose Metabolism

TCA Cycle Intermediate Catabolism

Some intermediates, such as citrate, can be partially oxidized, but Kreb's cycle intermediate catabolism requires leaving the cycle at oxaloacetate and then returning as acetyl-CoA. Note that this requires leaving the mitochondria for some reactions, and since the extremely low concentrations of oxaloacetate don't allow its efficient transport across the mitochondrial membrane (the Km of the carrier is much higher than [oxaloacetate]), malate is the species which actually leaves the mitochondria.

 

Regulation of the TCA Cycle

In order to understand the regulation of the TCA cycle we need to look at the DeltaG values for the various reactions and the kinetic properties of the enzymes. Values for the non-equilibrium reactions are tabulated below:

Data from E. A. Newsholme and A. R. Leach Biochemistry for the Medical Sciences. John Wiley & Sons, New York (1983) pp 101 & 110.

 Enzyme Substrate Substrate Conc. (mu (micro)M)  Km (mu (micro)M) DeltaG (kJ/mol)  Effectors
 Citrate synthase acetyl-CoA 100-600 5-10 -53.9
Succinyl CoA (-), ATP (-), NADH (-)
oxaloacetate 1-10 5-10
 Isocitrate DH (NAD+) isocitrate 150-700 50-200 -17.5
 Ca2+ (+), ATP (-), ADP(+), NADH (-)
 2-Oxoglutarate DH 2-oxoglutarate 600-5900 60-200 -43.9
 Ca2+ (+), Succinyl CoA (-), NADH (-)

Note that normally the concentrations of ATP, ADP, NAD+, and NADH are relatively constant in the mitosol and are thus unlikely to be very effective as allosteric regulators under most circumstances. On the other hand the availability of NAD+ and FAD as substrate will affect the rate not only of the reactions in the table, but also the near-equilibrium dehydrogenases. Note that NAD+ availability in turn is determined by the activity of the electron transport system, whose activity is closely coupled to the availability of ADP. Thus high [ATP] will slow the TCA cycle since high [ATP] means low [ADP], which will slow the ETS resulting in low [NAD+]!

In muscle, Ca2+ does show significant changes in concentration in the mitosol (recall that an increase in [Ca2+] concentration initiates muscle concentraction). Succinyl CoA will also show significant concentration changes under differing conditions and can thus also serve as an effective regulator, indicating carbon status in the second half of the cycle.

Regulation and Control: The concentration of citrate also affects PFK activity as a negative effector. You may want to review other aspects of control from last time.

Interconversion of metabolic intermediates: The TCA cycle has a central place in metabolism (even in anaerobic organisms) via its use to interconvert metabolites. We will look further at these interactions as the course proceeds.

Overview of Glucose Metabolism in the Tissues: Diagram in packet.

Metabolism of hexoses other than glucose–Glyc/Gluconeo Overview.

  1. Fructose
  2. Mannose
  3. Galactose on

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© R. A. Paselk 2010;

Last modified 3 April 2013