Glycolysis for Nurses

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Digestion of Dietary Carbohydrates

Dietary carbohydrates from which humans gain

energy enter the body in complex forms, such as

disaccharides and the polymers starch (amylose

and amylopectin) and glycogen. The polymer

cellulose is also consumed but not digested. The

first step in the metabolism of digestible

carbohydrate is the conversion of the higher

polymers to simpler, soluble forms that can betransported across the intestinal wall and

delivered to the tissues. The breakdown of

polymeric sugars begins in the mouth. Saliva has

a slightly acidic pH of 6.8 and contains lingual

amylase that begins the digestion of

carbohydrates. The action of lingual amylase islimited to the area of the mouth and the

esophagus; it is virtually inactivated by the much

stronger acid pH of the stomach. Once the food

has arrived in the stomach, acid hydrolysis

contributes to its degradation; specific gastric

proteases and lipases aid this process forproteins and fats, respectively. The mixture of

gastric secretions, saliva, and food, known

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collectively as chyme, moves to the small

intestine.

The main polymeric-carbohydrate digesting

enzyme of the small intestine is -amylase. This

enzyme is secreted by the pancreas and has the

same activity as salivary amylase, producing

disaccharides and trisaccharides. The latter are

converted to monosaccharides by intestinal

saccharidases, including maltases that hydrolyze

di- and trisaccharides, and the more specificdisaccharidases, sucrase, lactase, and trehalase.

The net result is the almost complete conversion

of digestible carbohydrate to its constituent

monosaccharides. The resultant glucose and

other simple carbohydrates are transported

across the intestinal wall to the hepatic portalvein and then to liver parenchymal cells and

other tissues. There they are converted to fatty

acids, amino acids, and glycogen, or else

oxidized by the various catabolic pathways of

cells.

Oxidation of glucose is known as glycolysis.Glucose is oxidized to either lactate or pyruvate.

Under aerobic conditions, the dominant product

in most tissues is pyruvate and the pathway is

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known as aerobic glycolysis. When oxygen is

depleted, as for instance during prolonged

vigorous exercise, the dominant glycolytic

product in many tissues is lactate and the

process is known as anaerobic glycolysis.

GLYCOLYSIS PATHWAY

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The Energy Derived from Glucose Oxidation

Aerobic glycolysis of glucose to pyruvate,

requires two equivalents of ATP to activate theprocess, with the subsequent production of four

equivalents of ATP and two equivalents of

NADH. Thus, conversion of one mole of

glucose to two moles of pyruvate is

accompanied by the net production of two moles

each of ATP and NADH.Glucose + 2 ADP + 2 NAD+ + 2 Pi -----> 2

Pyruvate + 2 ATP + 2 NADH + 2 H+

The NADH generated during glycolysis is used

to fuel mitochondrial ATP synthesis via

oxidative phosphorylation, producing either two

or three equivalents of ATP. (depending uponwhether the glycerol phosphate shuttle or the

malate-aspartate shuttle is used to transport the

electrons from cytoplasmic NADH into the

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mitochondria. The net yield from the oxidation

of 1 mole of glucose to 2 moles of pyruvate is,

therefore, either 6 or 8 moles of ATP. Complete

oxidation of the 2 moles of pyruvate, through the

TCA cycle, yeilds an additional 30 moles of

ATP; the total yield, therefore being either 36 or

38 moles of ATP from the complete oxidation of

1 mole of glucose to CO2 and H2O.)

Anaerobic Glycolysis

Under aerobic conditions, pyruvate in most cells

is further metabolized via the TCA cycle. Under

anaerobic conditions and in erythrocytes under

aerobic conditions, pyruvate is converted to

lactate by the enzyme lactate dehydrogenase

(LDH), and the lactate is transported out of thecell into the circulation. The conversion of

pyruvate to lactate, under anaerobic conditions,

provides the cell with a mechanism for the

oxidation of NADH (produced during the

G3PDH reaction) to NAD+; which occurs

during the LDH catalyzed reaction. Thisreduction is required since NAD+ is a necessary

substrate for G3PDH, without which glycolysis

will cease. Normally, during aerobic glycolysis

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the electrons of cytoplasmic NADH are

transferred to mitochondrial carriers of the

oxidative phosphorylation pathway generating a

continuous pool of cytoplasmic NAD+.

Aerobic glycolysis generates substantially more

ATP per mole of glucose oxidized than does

anaerobic glycolysis. The utility of anaerobic

glycolysis, to a muscle cell when it needs large

amounts of energy, stems from the fact that the

rate of ATP production from glycolysis isapproximately 100X faster than from oxidative

phosphorylation. During exertion muscle cells

do not need to energize anabolic reaction

pathways. The requirement is to generate the

maximum amount of ATP, for muscle

contraction, in the shortest time frame. This iswhy muscle cells derive almost all of the ATP

consumed during exertion from anaerobic

glycolysis.

The lactate produced during anaerobic

glycolysis diffuses from the tissues and is

transproted to highly aerobic tissues such ascardiac muscle and liver. The lactate is then

oxidized to pyruvate in these cells by LDH and

the pyruvate is further oxidized in the TCA

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cycle. If the energy level in these cells is high

the carbons of pyruvate will be diverted back to

glucose via the gluconeogenesis pathway.

Regulation of Glycolysis

. The rate limiting step in glycolysis is the

reaction catalyzed by PFK-1. The major sites for

regulation of glycolysis and gluconeogenesis are

the phosphofructokinase-1 (PFK-1) and

fructose-1,6-bisphosphatase (F-1,6-BPase)

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The ADH and AcDH catalyzed reactions also

leads to the reduction of NAD+ to NADH. The

metabolic effects of ethanol intoxication stem

from the actions of ADH and AcDH and the

resultant cellular imbalance in the

NADH/NAD+.

Regulation of Blood Glucose Levels

If for no other reason, it is because of the

demands of the brain for oxidizable glucose thatthe human body exquisitely regulates the level

of glucose circulating in the blood. This level is

maintained in the range of 5mM.

SOURCE OF GLUCOSE

Nearly all carbohydrates ingested in the diet

are converted to glucose following transport

to the liver.

Catabolism of dietary or cellular proteins

generates carbon atoms that can be utilized

for glucose synthesis via gluconeogenesis.

Other tissues besides the liver that

incompletely oxidize glucose

(predominantly skeletal muscle and

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erythrocytes) provide lactate that can be

converted to glucose via gluconeogenesis.

GLUCOSE HOMEOSTASIS

Maintenance of blood glucose homeostasis is of

paramount importance to the survival of the

human organism. The predominant tissue

responding to signals that indicate reduced or

elevated blood glucose levels is the liver.

Indeed, one of the most important functions of

the liver is to produce glucose for the

circulation. Both elevated and reduced levels of

blood glucose trigger hormonal responses to

initiate pathways designed to restore glucose

homeostasis.

Low blood glucose triggers release of glucagon

from pancreatic -cells. Glucagon binds to its'

receptors on the surface of liver cells leading to

an increased rate ofglycogenolysis by activatingglycogen phosphorylase. This is the same

response hepatocytes have to epinephrine

release. The resultant increased levels of G6P in

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hepatocytes is hydrolyzed to free glucose, by

glucose-6-phosphatase, which then diffuses to

the blood.

High blood glucose triggers release of insulin

from pancreatic -cells. In opposition to the

cellular responses to glucagon (and epinephrine

on hepatocytes), insulin stimulates extrahepatic

uptake of glucose from the blood and inhibits

glycogenolysis in extrahepatic cells andconversely stimulates glycogen synthesis. As the

glucose enters hepatocytes it binds to and

inhibits glycogen phosphorylase activity. Why is

it that the glucose that enters hepatocytes is not

immediately phosphorylated and oxidized?

Liver cells contain an isoform of hexokinasecalled glucokinase. Glucokinase has a much

lower affinity for glucose than does hexokinase.

Therefore, it is not fully active at the

physiological ranges of blood glucose.

Additionally, glucokinase is not inhibited by its

product G6P, whereas, hexokinase is inhibitedby G6P.

One major response of non-hepatic tissues to

insulin is the recruitment, to the cell surface, of

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glucose transporter complexes. Glucose

transporters comprise a family of five members,

GLUT-1 to GLUT-5. GLUT-1 is ubiquitously

distributed in various tissues. GLUT-2 is found

primarily in intestine, kidney and liver. GLUT-3

is also found in the intestine and GLUT-5 in the

brain and testis. GLUT-5 is also the major

glucose transporter present in the membrane of

the endoplasmic reticulum (ER) and serves the

function of transporting glucose to the cytosolfollowing its' dephosphorylation by the ER

enzyme glucose 6-phosphatase. Insulin-sensitive

tissues such as skeletal muscle and adipose

tissue contain GLUT-4. When the concentration

of blood glucose increases in response to food

intake, pancreatic GLUT-2 molecules mediatean increase in glucose uptake which leads to

increased insulin secretion. Recent evidence has

shown that the cell surface receptor for the

human T cell leukemia virus (HTLV) is the

ubiquitous GLUT-1.

Hepatocytes, unlike most other cells, are freely permeable to glucose and are, therefore,

essentially unaffected by the action of insulin at

the level of increased glucose uptake. When

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blood glucose levels are low the liver does not

compete with other tissues for glucose since the

extrahepatic uptake of glucose is stimulated in

response to insulin. Conversely, when blood

glucose levels are high extrahepatic needs are

satisfied and the liver takes up glucose for

conversion into glycogen for future needs.

Under conditions of high blood glucose, liver

glucose levels will be high and the activity of

glucokinase will be elevated. The G6P producedby glucokinase is rapidly converted to G1P by

phosphoglucomutase, where it can then be

incorporated into glycogen

Additional signals, ACTH (adrenocorticotrophic

hormone - a peptide hormone that is produced

by the anteriorpituitary gland. It stimulates the

adrenal cortex to secrete glucocorticoid

hormones, which help cells synthesize glucose)

and growth hormone, released from the pituitary

act to increase blood glucose by inhibiting

uptake by extrahepatic tissues.

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The glucose from liver (ie. from

gluconeogenesis or glycogenolysis) enters

extrahepatic cells where it is re-phosphorylated

by hexokinase. Since muscle and brain cells lack

glucose-6-phosphatase, the glucose-6-phosphate

product of hexokinase is retained and oxidized

by these tissues.

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