Anaplerotic sequences:

Anaplerotic (meaning "filling up" in Greek) pathways replace lost carbon compounds that are drawn out of central metabolism to produce other cell constituents.

PEP

pyruvate

Ac-CoA

  Asp <--  OAA                              citrate  --> F. A.

TCA cycle
pyr  -->  malate             (mito)              a-KG --> Glu

succ-CoA

heme, chlorophyll

Anaplerotic reactions:

1. pyruvate carboxylase --> (activated by acetyl-CoA; almost inactive without it):

pyruvate + ATP + HCO₃^- <===> OAA + ADP + P + H⁺

2. PEP carboxylase (in plants and bacteria)

PEP + HCO₃^- ----> OAA + P_i

3. malate dehydrogenase

pyruvate + HCO₃^- + NADPH + H⁺ ----> malate + NADP⁺ + H₂O

Pentose phosphate pathway:

Remember the rule of thumb that NADH functions in energy metabolism and that NADPH is involved in biosynthesis.

Overall reaction:

Glucose 6-phosphate + 2 NADP⁺ + H₂O --> ribose 5- phosphate + 2 NADPH + 2H⁺ + CO₂

pentose phosphate pathway provides:

a. NADPH for fatty acid synthesis and other reductive synthetic reactions
b. Ribose 5-phosphate for ATP, CoA, NADH, FAD, RNA, DNA

This pathway is prominent in tissues where fatty acid or sterol synthesis is active (liver, adipose tissue (including mammary gland), and adrenal cortex).

Groups of reactions:

The sequence of reactions can be broken down into three reaction categories: (very similar to TCA except first two classes are reversed!)

a. dehydrogenation/decarboxylation
b. isomerization
c. rearrangement

Rearrangement Reactions:
Up to this point we have assumed that ribose (for RNA and DNA + coenzymes) is needed in exactly the same amounts as NADPH. What happens if more NADPH is needed? There must be a part of the pathway that converts ribose 5-P to an intermediate in another b iochemical pathway (glycolysis and fructose-6-P, in this case).

Schematically, these reactions proceed as follows:

C5 + C5 < ==> C3 + C7
coenzyme = TPP; transketolase

C7 + C3 < ==> C4 + C6
Schiff's base with e-amino of lysine; transaldolase

C5 + C4 < ==> C3 + C6
coenzyme = TPP; transketolase

3 C5 ==> 2 C6 + C3 (Sum total)

Regulation of the pathway occurs at glucose 6-phosphate dehydrogenase (first committed, i.e. irreversible step into this pathway). NADPH, if in excess, competes for NADP+ binding site, therefore NADPH generation is tightly linked to its utilization in reduc tive biosynthesis.

Metabolic conditions:

A. More ribose 5-P needed than NADPH: transadlolases and transketolases take C6 and C3 from glycolytic pathway --> C5

B. More NADPH needed than ribose: recycle the C6 and C3 formed in rearrangement rxns --> ultimately C6 ---> 6 CO2

C. Need NADPH and ATP, but not much ribose: ribose --> C3 and C6 --> pyruvate + ATP

Hemolytic anemia:

Hemolytic anemia was identified in World War II, when primaquinone was used to fight malaria (caused by plasmodium falciparum). At the level of biochemistry, a deficiency in glucose 6-phosphate dehydrogenase produces hemolytic anemia.

This enzyme is the only source of NADPH in the red blood cells (they lack mitochondria). With no NADPH, glutathione in the red blood cells cannot be maintained in its reduced form.

Normally, the ratio of GSH to GSSG is about 500 to 1; this keeps heme and possibly Fe in a reduced state. As Fe²⁺ is converted to Fe³⁺ hemoglobin can't bind oxygen, peroxides may build up and cause damage to membrane lipids. This results in weakening the membrane and a subsequent rupture of the red blood cells.