Hexose Monophospahte Pathway Flashcards
The Hexose Monophosphate Pathway (HMP) begins with
Glucose-6-Phosphate
HMP’s principal purpose is the production of the cell’s basic anabolic reducing power, reduced
NADPH
The secondary purpose of the HMP is the synthesis of
Ribose-5-Phosphate (R5P)
Seven, six, five and four carbon compounds are
HMP intermediates
These sugar intermediates can enter the pathway directly from the diet, as well via G6P and by salvage of pentoses produced by catabolism of cellular constituents such as
Nucleotides and Glucuronic Acid
Likewise, these intermediates may be siphoned off for other biosynthetic purposes. Their principal fate is as precursors in
Glycolysis
The primary mechanism for the regulation of this pathway involves the cell’s need for
NADPH
The primary mechanism for the regulation of this pathway involves the cell’s need for NADPH, exerting its effect upon the first enzyme in the pathway
G-6-P Dehydrogenase
Takes place in the cytoplasm of all cell types
HMP
Because there are alternative routes for R5P synthesis, most pathology associated with defects in this pathway are attributable to a diminished supply of
Reducing Power (NADPH)
What are the two phases to the HMP?
- ) Oxidative Phase
2. ) Non-oxidative (sugar-interconversion) phase
Neither phase utilizes
ATP
There are three irreversible steps in the oxidative phase, followed by the isomerization of ribulose 5-phosphate to
Ribose-5-Phosphate
It is the #1 carbon of G6P that is recovered as
CO2
Unless the cell requires R5P as precursor for other specific biosynthetic processes it is further metabolized by a series of sugar interconversions, ultimately producing precursors for glycolysis in the
Non-oxidative phase
The reactions catalyzed in the nonoxidative phase are all
Reversible
In the non-oxidative phase, Ribulose 5-P is isomerized to produce ribose 5-P, and it is also epimerized to produce
Xylulose 5-P
After three additional reactions, first with a transketolase, then a transaldolase, and concluding with again with transketolase, we arrive at
Glycolysis intermediates
Which two glycolysis intermediates does the non-oxidative phase produce?
Glyceraldehyde-3-phosphate and fructose-6-phosphate
The starting material for the HMP is
3 moles of G-6-P
What are the 4 end products of the HMP?
- ) 3 CO2
- ) 6 NADPH
- ) 2 F-6-P
- ) 1 Glyceraldehyde-3-P
When the cell needs more NADPH than it does R-5-P, we use the glyceraldehyde and F-6-P products to synthesize
G-6-P
This G-6-P can be used to produce how many NADPH
12
This is a likely scenario in cells where there is a considerable need for NADPH, such as in the synthesis of
Fatty Acids
When the cell needs equal amounts of NADPH and R-5-P, what happens?
HMP “halts” with conclusion of oxidative phase
In this scenario, no sugar interconversions occur because R5P is utilized in other processes before it can be acted on by
Transketolase
This might commonly occur in rapidly dividing cells with the need to replicate the genomic material
Needing more R-5-P than NADPH
Because the sugar-interconversion reactions are reversible, it is possible to synthesize R5P from
Glycolytic Intermediates
What happens when the cell requires more NADPH than it does R5P but does not have the luxury of performing gluconeogenesis (I.e. the cell needs more ATP)?
In this case the sugar-interconversion phase fully converts R5P to glycolytic precursors
Sometimes, the cell needs more NADPH than it does R-5-P but it can not undergo gluconeogenesis. In this case the sugar-interconversion phase fully converts R5P to glycolytic precursors which then act as substrate in the
TCA cycle
This occurs via pyruvate, with the concamitant synthesis of
2 moles ATP per mole of acetyl-CoA
The rate limiting step in the HMP is the first one, catalyzed by
Glucose-6-phosphate Dehydrogenase (G6PDH)
G6PDH is, in the short term, principally regulated in a negative feedback manner by
NADPH
Long term regulation occurs at the level of transcription of the gene encoding G6PDH, and is influenced positively by
Insulin
The cell’s principal currency in anabolic reducing power
NADPH
Its synthesis is the basis for our dietary requirement for
Niacin/Nicotinamide
Able to donate TWO so-called reducing equivalents
NADPH
In contrast to NADH, made during glycolysis and the TCA cycle and used in the process of oxidative phosphorylation, NADPH is NOT associated with
Oxidative Phosphorylation or ATP synthesis
Required in several phases of fatty acid synthesis
NADPH
Production of the major product of fatty acid synthesis, palmitate, a 16 carbon fatty acid requires
14 molecules of NADPH
Required at two different points in the process of cholesterol biosynthesis
NADPH
The synthesis of mevalonate from 3-hydroxy-3-methylglutaryl CoA requires
2 NADPH
Hydroxylation of cholesterol to certain steroid hormones also requires NADPH, in a process involving the
P-450 System
Conversion of the ribose unit of nucleotides to the deoxyribose form is a multi-step process that begins with
NADPH
Ribose is converted to deoxyribose by the enzyme
Ribonucleotide reductase
NADPH is also required for the conversion of
dUMP to dTMP
Over 100 isozymes are members of this “superfamily” of mono-oxygenases with specificities for the oxidation of steroids, carcinogens, drugs or xenobiotic substances
Cytochrome P-450 enzymes
The aim of the P-450 system is to recognize, solubilize and thereby promote the removal of such foreign materials from the body via
The Kidneys
A variety of chemical transformations are possible among the array of P-450 enzymes, but they all have in common the reaction of a single oxygen with either a
Carbon, Sulfur, or Nitrogen
What is NADPH’s role in the P-450 system?
Reduces iron from Fe3+ to Fe2+ at two points in the cycle
Reducing power is transferred to the cytochrome by an intermediary called the
-a membrane bound enzyme
NADPH-Cytochrome P-450 reductase
The P-450 system functions best with substrates with some
Hydrophobicity
In addition to functioning in drug and xenobiotic removal, specific P-450 enzymes are used in the biosynthesis of
Steroid Hormones
Catalyzes a reaction from cigarette smoke that is actually dangerous to humans
P-450 system
The chemical process by which granulocytes (macrophages, neutrophils and eosinophils) destroy invading microorganisms is initiated by
NADPH oxidase
Forms superoxide form NADPH and O2
NADPH oxidase
NADPH oxidase forms superoxide (a free-radical form of oxygen) from NADPH and O2 with the consumption of O2. This is referred to as a
Respiratory Burst
Converts superoxide to hydrogen peroxide
Superoxide dismutase
Genetic defects in the NADPH oxidase leads to
-Reduces the hosts ability to fight bacterial infections
Granulomatous Disease
A tripeptide present in high concentrations in all cell types and functions to protect cellular components from the reactive peroxides
Glutathione
Reduced glutathione (GSH) reacts with peroxide to form
Water
Regeneration of GSH requires NADPH and the enzyme
Glutathione reductase
Catalyzes the conversion of arginine and O2 to citruline and NO, requiring one NADPH in the process
NO-synthetase
This pathway possibly accounts for a considerable portion of the body’s use of
NADPH
One of the precursors in the biosynthesis of aromatic amino acids
Erythrose 4-phosphate
A prosthetic group in the transketolase functioning in the non-oxidative phase of the HMP
Thiamine Pyrophosphate (TPP)
Covalently bound to the two carbon unit that is exchanged in the transketolase reaction
TPP
Transketolase that lacks TPP is
Inactive
Individuals harboring mutations in transketolase that reduce its affinity for TPP can display a series of symptoms that are in aggregate referred to as the
Wernicke-Korsakoff Syndrome (WKS)
In large part, the symptomology is neurological, ranging from depression, irritability and fatigue to
Confusion, ataxia, and opthalmoplegia
Most commonly seen in chronic alcoholics, presumably due to poor absorption of the vitamin
Wernicke-Korsakoff Syndrome (WKS)
Represents the most prevalent enzymopathy in human populations, where as many as 400 million people world wide are deficient
G6PDH Deficiency
10-25% of tropical African populations, 1-3% of some Mediterranean populations, and 5-10% of tropical and sub-tropical Asian populations are affected by
G6pDH deficiency
Defects in transketolase do not have an immediate influence upon the production of
NADPH
However, defects in G6PDH drastically affect the production of
NADPH
G6PDH deficiency presents as a form of
Hemolytic anemia
Can be induced by the ingestion of the fava bean
G6PDH
Deficiency for G6PDH in red blood cells (RBC) severely restricts its ability to generate
NADPH
When ROS build up in RBCs they can react with hemoglobin, which results in the precipitation of
Heinz bodies
The G6PDH gene is located on the
X-chromosome
An example of a class IV enzyme; it shows an alteration in electrophoretic mobility, but no significant difference in its enzymatic properties
G6PDH A variant
More severe, and do show clinical symptoms, albeit rarely and under specific circumstances
Class III mutations
A member of class III mutations
G6PDH A- varient
Higher up on the scale of severity is the G6PD Mediterranean, categorized in
Class II
The Mediterranean variant shows normal enzyme activity, but is present in much reduced levels in the
RBC
Lastly, class I mutations are the most severe, with chronic anemia. These most severe deficiencies in G6PDH activity have a condition called
Nonspherocytic anemia
There is a link between the presence of mutations in G6PDH and resistance to
Malaria
Ironically, individuals with G6PDH deficiency may show the characteristic hemolytic response to the anti-malarial drug
Primaquine
In lipid synthesizing cells of the adipose, mammary gland and liver as much as 70% of the NADPH produced comes from the so-called
-The reason G6PDH deficiency does not always show severe symptoms
Malic Enzyme
NADPH can also be produced from NADH in the mitochondrion, by means of
Nicotinamide Nucleotide Transhydrogenase
