Metabolism of Monosaccharides and Disaccharides; PPP

Question 1

Entry points of sugars into glycolysis

(Chart/Big Picture/General Idea)

Answer 1

Question 2

Sucrose is a disaccharide of ____ and ____

Answer 2

Sucrose is a disaccharide of fructose and glucose

Question 3

Fructose can be found in the following sources (5 examples)

Answer 3

Frucoste can be found in the following sources:

• Table sugar
• Sugar cane
• Fruits/Fruit sugar
• Honey (50% fructose)
• High fructose corn syrup (55% fructose and 45% glucose)

Note: Sucrose is a disaccharide made from fructose and glucose

Question 4

____ (in all tissues) converts fructose to fructose-6-phosphate; this enzyme has a high Km (low affinity) for fructose

____ (found in liver, kidney, and small intestine) converts fructose to fructose-1-phosphate and has a very low Km (high affinity), high Vmax, and rapidly phosphorylates fructose

Answer 4

Hexokinase (in all tissues) converts fructose to fructose-6-phosphate; this enzyme has a high Km (low affinity) for fructose

Fructokinase (found in liver, kidney, and small intestine) converts fructose to fructose-1-phosphate and has a very low Km (high affinity), high Vmax, and rapidly phosphorylates fructose

Question 5

Why is fructose metabolism to trioses more rapid than glucose metabolism?

Answer 5

Because it bypasses the rate limiting step of glycolysis which is PFK-1 (phosphofructokinase-1)

Question 6

The metabolism of fructose occurs principally in the ____

Fructose-1-phosphate is cleaved into ____ and ____ by ____

Answer 6

The metabolism of fructose occurs principally in the ____

Fructose-1-phosphate is cleaved into ____ and ____ by ____

Question 7

There are ____ aldolase isoforms which are __, __, and __; all are able to cleave ____

Answer 7

There are three aldolase isoforms which are A, B, and C; all are able to cleave fructose-1,6-bisphosphate

Question 8

Aldolase A is present present in ____ and most other tissues; it can cleave ____ but it cannot leave ____

Answer 8

Aldolase A is present present in muscle and most other tissues; it can cleave fructose-1,6-bisphosphate but it cannot leave Fructose-1-Phosphate

Question 9

Alsolase B is only prsesent in the ____, kidney, and small intestines; it can cleave ____ and ____

Answer 9

Alsolase B is only prsesent in the liver, kidney, and small intestines; it can cleave fructose-1-phosphate and fructose-1,6-bisphosphate

Question 10

Aldolase C is ubiquitously expressed in most tissues, though it is predominantly expressed in the ____; can cleave ____ but cannot cleave ____

Answer 10

Aldolase C is ubiquitously expressed in most tissues, though it is predominantly expressed in the brain; can cleave fructose-1,6-bisphosphate but cannot cleave fructose-1-phosphate

Question 11

Aldolase A, B, and C can all cleave fructose 1,6-bisphosphate; which aldolases cannot cleeave F-1-P?

Answer 11

Aldolase A and Aldolase C cannot cleave F-1-P

Question 12

Glyceraldehyde 3-phosphate can be used as glycolytic intermediates but can also be used for ____ to produce glucose

Answer 12

Glyceraldehyde 3-phosphate can be used as glycolytic intermediates but can also be used for gluconeogenesis to produce glucose

Question 13

In liver, aldolase __ is highly expressed whereas aldolase __ and __ expression is much lower. Therefor aldolase __ is critical for fructose metabolism as well as gluconeogenesis

Answer 13

In liver, aldolase B is highly expressed whereas aldolase A and C expression is much lower. Therefor aldolase B is critical for fructose metabolism as well as gluconeogenesis

Question 14

Essential Fructoseria

Lack of ____

Autosomal ____

Benign condition that results in ____ in the urine

Answer 14

Essential Fructoseria

Lack of fructokinase

Autosomal recssive

Benign condition that results in fructose in the urine

Question 15

Hereditary Fructose Intolerance (“Fructose Poisoning”)

Absence of ____ leads to intracellular trapping of ____

Autosomal ____

Fructose/sucrose/sorbitol can cause ________ (may see elevated ____) and death

Also causes (8 examples):

Therapy: rapid detection and removal of ____ and ____ from the diet

Answer 15

Hereditary Fructose Intolerance (“Fructose Poisoning”)

Absence of aldolase B leads to intracellular trapping of fructose 1-phosphate

Autosomal ressive

Fructose/sucrose/sorbitol can cause hepatic failure (may see elevated ALT/AST) and death

Also causes (8 examples):

• Severe hypoglycemia
• Vomiting
• Jaundice
• Hepatomegaly
• Hemorrhage
• Renal dysfunctions
• Hyperuricemia
• Lacticacidemia

Therapy: rapid detection and removal of fructose and sucrose from the diet

Question 16

Hereditary Fructose Intolerance (“Fructose Poisoning”)

First appears when baby is weaned from milk and is fed food containing ____ or ____

____ accumulates, resulting in the a drop of the inorganic phosphate (Pi) levels, therfore a drop in ____ production. This drop in Pi also inhibits ____.

As ____ falls, AMP rises and is degraded, causing hyperuricemia and lactic acidemia

Decrease of available ____ also decreases ____ (causing hypoglycemia with vomiting) and decreases ________ (causing a decrease in blood clotting factors and other essential proteins)

Answer 16

Hereditary Fructose Intolerance (“Fructose Poisoning”)

First appears when baby is weaned from milk and is fed food containing sucrose or fructose

Fructose 1-phosphate accumulates, resulting in the a drop of the inorganic phosphate (Pi) levels, therfore a drop in APT production. This drop in Pi also inhibits glycogenolysis.

As ATP falls, AMP rises and is degraded, causing hyperuricemia and lactic acidemia

Decrease of available ATP also decreases gluconeogenesis (causing hypoglycemia with vomiting) and decreases protein synthesis (causing a decrease in blood clotting factors and other essential proteins)

Question 17

Sources of galactose

Answer 17

• Dairy products
• Blackeyed peas
• Sugar beets
• Some beans

Question 18

____ is a disaccharide of galactose and glucose

Capacity to metabolize galactose in infants is higher than adults

Galactose

Answer 18

Lactose is a disaccharide of galactose and glucose

Capacity to metabolize galactose in infants is higher than adults

Galactose

Question 19

Galactokinase Deficiency

Rare autossomal ____ disorder

Causes elevation of ____ in blood (called ____) and urine (called ____)

Causes ____ accumulation if ____ is present in the diet

Elevated ____ can cause cateracts

Treatment is dietary restriction

Answer 19

Galactokinase Deficiency

Rare autossomal ressive disorder

Causes elevation of galactose in blood (called galactosemia) and urine (called galactosuria)

Causes galactitol accumulation if galactose is present in the diet

Elevated galactitol can cause cateracts

Treatment is dietary restriction

Question 20

Classic Galactosemia

________ deficiency

Autosomal ____

Causes ____, ____, ____, ____, and ____

Accumulation of ____ and ____ in nerve/lens/liver/kidney tissue causes liver damage, severe mental retardation, and ____

Prenatal diagnosis is possible by chorionic villus sampling; newborn screen also available

Therapy: Rapid diagnosis and removal of ____ (and therefore ____) from diet

Despite adequate treatment, at risk for developmental delays, and in fameles, premature ovarian failure

Answer 20

Classic Galactosemia

Galactose 1-phosphate uridyltransferase (GALT) deficiency

Autosomal recessive

Causes galactosemia, galactosuria, vomiting, diarrhea, and jaundice

Accumulation of galactose 1-phosphate and galactitol in nerve/lens/liver/kidney tissue causes liver damage, severe mental retardation, and cataracts

Prenatal diagnosis is possible by chorionic villus sampling; newborn screen also available

Therapy: Rapid diagnosis and removal of galactose (and therefore lactose) from diet

Despite adequate treatment, at risk for developmental delays, and in fameles, premature ovarian failure

Question 21

________ converts galactose (when accumulated due to a deficiency) into galactitol

Elevated galactitol levels can cause ____

Answer 21

Aldose Reductase converts galactose (when accumulated due to a deficiency) into galactitol

Elevated galactitol levels can cause cataracts

Question 22

The Polyol Pathway for synthesis of fructose from glucose can lead to pathological ____ accumulation

Answer 22

The Polyol Pathway for synthesis of fructose from glucose can lead to pathological sorbitol accumulation

Question 23

Aldoase Reductase converts:

Aldoses to ____

Galactose to ____

Glucose to ____

Answer 23

Aldoase Reductase converts:

Aldoses to alcohols

Galactose to galactitol

Glucose to sorbitol

Question 24

Sorbitol dehydrogenase converts ____ to ____

Answer 24

Sorbitol dehydrogenase converts sorbitol to fructose

Question 25

Sorbitol dehydrogenase is low or absent in \_\_\_\_, \_\_\_\_, kidney, and nerve cells, which exacerbates sorbitol accumulation In hyperglycemia/hypergalactosemia (and adequate NADPH), ____ and ____ accumulate in the \_\_\_\_\_\_\_\_, kidney, and nerve cells, causing increased osmotic pressure Some of the pathologic alterations asssociated with diabetes, including ____ formation, peripheral neuropahty, and microvascular problems leading to nephropathy and retinapthy, can be attributed, in part, to this

Answer 25

Sorbitol dehydrogenase is low or absent in _retina_, _lens_, kidney, and nerve cells, which exacerbates sorbitol accumulation In hyperglycemia/hypergalactosemia (and adequate NADPH), _sorbitol_ and _galactitol_ accumulate in the _lens of the eye_, kidney, and nerve cells, causing increased osmotic pressure Some of the pathologic alterations asssociated with diabetes, including _cataract_ formation, peripheral neuropahty, and microvascular problems leading to nephropathy and retinapthy, can be attributed, in part, to this

Question 26

The Pentose Phosphate Pathway helps to supply ________ and \_\_\_\_ It is sometimes also called the ________ or \_\_\_\_\_\_\_\_

Answer 26

The Pentose Phosphate Pathway helps to supply _sugar variety_ and _NADPH_ It is sometimes also called the _Hexose Monophosphate Shunt_ or _Phosphate Shunt_

Question 27

What are the two processes that produce NADPH?

Answer 27

* Pentose Phosphate Pathway (major producer of NADPH) * Citrate Shuttle (related to fatty acid metabolism)

Question 28

NADPH is a reducting agent involved in ____ reactions in biosynthetic pathways and ____ reactions NADPH is important in (2 main examples):

Answer 28

NADPH is a reducting agent involved in _redox_ reactions in biosynthetic pathways and _detoxification_ reactions NADPH is important in: * **Reduction of Hydrogen Peroxide (glutathione defense system)** * **Phagocytosis by WBCs** * Fatty acid and steroid synthesis * Cytohrome P450 monooxygenase system * Synthesis of nitric oxide (NO)

Question 29

What are the two phases of the Pentose Phosphate Pathway and what do they do?

Answer 29

* **The Oxidative Phase**: _Generates NADPH_ required for biosynthetic pathways and ROS detoxification * **The Nonoxidative Phase**: Interconverts monosaccharides to produce _ribose-5P for nucleotide synthesis_, and also _regnerates glucose-6P to maintain NADPH production_ by the oxidative phase

Question 30

What are the key enzymes in the Pentose Phosphate Pathway and why are they important?

Answer 30

**Glucose-6P dehydrogenase**: Committed Step; occurs in oxidative phase; is feedback inhibited by NADPH **Transketolase and Transaldolase**: These two enzymes catalyze reversible "carbon shuffle" reaction of the nonoxidative phase

Question 31

When phosphofructokinase (the controlling enzyme for glycolysis) is inactive, where is glucose 6-phosphate diverted into?

Answer 31

The Pentose Phosphate Pathway

Question 32

RBC's derive their energy by converting glucose into 2 molecules of ____ and 2 molecules of \_\_\_\_ 10% of glucose entering RBCs going into the PPP to generate \_\_\_\_, which is required to keep ____ in the reduced state (this is essential to maintain membrane integrity) Mutations affecting ____ production in RBC's leads to ____ anemia

Answer 32

RBC's derive their energy by converting glucose into 2 molecules of _lactate_ and 2 molecules of _ATP_ 10% of glucose entering RBCs going into the PPP to generate _NADPH_, which is required to keep _glutathione_ in the reduced state (this is essential to maintain membrane integrity) Mutations affecting _NADPH_ production in RBC's leads to _hemolytic_ anemia

Question 33

**G6PDH Deficiency** \_\_\_\_\_\_\_\_ hereditary disease Characterized by ____ anemia caused by the inability to detoxify oxidizing agents. Can also cause neonatal jaundice 1-4 days after birth. Most common disease producing enzyme abnormality. Highest prevalence in middle east, tropical africa, and asia. Gives an increased resistance to \_\_\_\_\_\_\_\_

Answer 33

**G6PDH Deficiency** _X-linked_ hereditary disease Characterized by _hemolytic_ anemia caused by the inability to detoxify oxidizing agents. Can also cause neonatal jaundice 1-4 days after birth. Most common disease producing enzyme abnormality. Highest prevalence in middle east, tropical africa, and asia. Gives an increased resistance to _Plasmodium falciparum malaria_

Question 34

**Glutathione Defence System** Glutathione (GSH) is necessary for the removal of ____ and ________ generated by ROS Upon neutralizing ____ and \_\_\_\_, two glutathione (GSH) are oxidized together producing \_\_\_\_ \_\_\_\_ is used for the reduction of oxidized ____ to reduce to glutathione (GSH)

Answer 34

**Glutathione Defence System** Glutathione (GSH) is necessary for the removal of _H2O2_ and _lipid peroxides_ generated by ROS Upon neutralizing _H2O2_ and _peroxides_, two glutathione (GSH) are oxidized together producing _GSSG_ _NADPH_ is used for the reduction of oxidized _GSSG_ to reduce to glutathione (GSH)

Question 35

In RBCs, generation of superoxide ion from nonenzymatic oxidation of Hgb provides source of ROS The glutathione defense system if compramised by ________ deficiency, infections, certain drugs, and purine glycosides of fava beans As a consequence ________ (aggregates of cross-linked Hgb) form on the cell membranes. Causes mechanical stress, which along with ROS on the cell membrane causes \_\_\_\_

Answer 35

In RBCs, generation of superoxide ion from nonenzymatic oxidation of Hgb provides source of ROS The glutathione defense system if compramised by _glucose-6-phosphate ddehydrogenase_ deficiency, infections, certain drugs, and purine glycosides of fava beans As a consequence _Heinz bodies_ (aggregates of cross-linked Hgb) form on the cell membranes. Causes mechanical stress, which along with ROS on the cell membrane causes _hemolysis_ (hemolytic anemia)

Question 36

Most glucose-6-phosphate dehydrogenase deficient individuals are asymptomatic but can undergo an episode of hemolytic anemia if they are exposed to certain antimalarial drugs such as \_\_\_\_, \_\_\_\_, and \_\_\_\_, or if they eat \_\_\_\_\_\_\_\_

Answer 36

Most glucose-6-phosphate dehydrogenase deficient individuals are asymptomatic but can undergo an episode of hemolytic anemia if they are exposed to certain antimalarial drugs such as _primaquine_, _pamaquine_, and _chloroquine_, or if they eat _fava beans_

Question 37

Uses of NADPH (general idea)

Answer 37

**Uses of NADPH**: * **Phagocytosis by WBCs** * **Synthesis of NO (nitric oxide)** * **Cytochrome P450 monooxygenase system** * **Protection against oxidative stress by Glutathione preoxidase** * Reductive biosynthesis (e.g. Fatty acid synthesis, sterols, steroids) * Maintenance of reduced glutathione * Reduction of hydrogen peroxide

Question 38

**NADPH in Phagocytosis** \_\_\_\_\_\_\_\_ converts O2 into superoxide radical O2- (also known as respiratory burst or oxidative burst) O2- can react with water to form ____ to create either OH• radicals, or hypochlorous acid (HOCl), both of which are toxic to microorganisms

Answer 38

**NADPH in Phagocytosis** _NADPH oxidase_ converts O2 into superoxide radical O2- (also known as respiratory burst or oxidative burst) O2- can react with water to form _hydrogen peroxide (H2O2)_ to create either OH• radicals, or hypochlorous acid (HOCl), both of which are toxic to microorganisms

Question 39

**NADPH in Nitric Oxide synthesis** Nitric Oxide (NO) is a potent \_\_\_\_\_\_\_\_ It is also a neurotransmitter, decreases platelet aggregation, and hass a role in macrophage function NO is synthesized by ________ from arginine, O2, and **NADPH**

Answer 39

**NADPH in Nitric Oxide synthesis** Nitric Oxide (NO) is a _potent vasodilator_ It is also a neurotransmitter, decreases platelet aggregation, and hass a role in macrophage function NO is synthesized by _NO synthase (NOS)_ from arginine, O2, and **NADPH**

Question 40

**Non-oxidative reactions of the pentose phosphate pathway** Involves ____ (requires TPP from thiamine) and ____ reactions Non-oxidative reactions are \_\_\_\_

Answer 40

**Non-oxidative reactions of the pentose phosphate pathway** Involves _transketolase_ (requires TPP from thiamine) and _transaldolase_ reactions Non-oxidative reactions are _reversible_

Question 41

Transketolases require ____ from \_\_\_\_ RBC transketolase activity can be used to assay ____ deficiency

Answer 41

Transketolases require _TPP_ from _thiamine_ RBC transketolase activity can be used to assay _thiamine_ deficiency

Question 42

What are some main causes of microcytic anemia?

Answer 42

* Hypochromatic anemia * **Iron deficiency** * **Thalassemia** * Anemia of chronic disease * Sideroblastic Anemia (Lead) * Spherocytosis) Just know the ones we've learned so far (bolded above)

Question 43

What are some main causes of macrocytic anemia?

Answer 43

* **Magaloblastic anemia** * **Pernicious anemia (lack of intrinsic factor for B12 absorption)** * **Vitamin B12 deficiency** * **Folate deficiency** * **Methotrexate** * Pyrimidine synthesis deficiency * 5-Fluorouracil Just know the ones we've learned so far (bolded above)

Question 44

What are some main causes of normocytic anemia?

Answer 44

* **G6PD Deficiency** * **Pyruvate Kinase deficiency** * **Protein-energy malnutrition (Kwashiorkor)** * **Blood loss**

Question 45

What are some conditions that can alter RBC shape?

Answer 45

* Sickle cell anemia * Hemoglobin C