Module 3 Flashcards
– is the term used to describe the interconversion of
chemical compounds in the body, the pathways taken by individual molecules, their interrelationships, and the mechanisms that regulate the flow of metabolites through the pathways
Metabolism
Metabolic pathways fall into three categories.
- Anabolic pathways
- Catabolic pathways
- Amphibolic pathways
- are those involved in the synthesis of larger and more complex compounds from smaller precursor
- -for example, the synthesis of protein from amino acids and the synthesis of reserves of triacylglycerol and glycogen
Anabolic pathways
- are involved in the breakdown of larger molecules, commonly involving oxidative reactions
- they are exothermic, producing reducing equivalents, and, mainly via the respiratory chain
Catabolic pathways
– occur at the “crossroads” of metabolism, acting as links between the anabolic and catabolic pathways, for example, the citric acid cycle
Amphibolic pathways
energy requirement for human being is met from ____
carbohydrates (40%-60%)
lipids (mainly triacylglycerol, 30%-40%)
protein (10%-15%)
If the intake of metabolic fuels is consistently greater than
energy expenditure, the surplus is stored, largely as triacylglycerol in adipose tissue, leading to the development of ____
obesity
if the intake of metabolic fuels is consistently lower than energy expenditure, there are negligible reserves of fat and carbohydrate, and amino acids arising from protein turnover are used for energy-yielding metabolism rather than replacement protein synthesis, leading to _____
emaciation, wasting, and, eventually, death
– ample supply of carbohydrate, and the metabolic fuel for most tissues is glucose
Fed State
In the ___, glucose must be spared for use by the central nervous system (which is largely dependent on glucose) and the red blood cells (which are wholly reliant on glucose)
fasting state
As glycogen reserves become depleted (in fasting state), amino acids arising from protein turnover are used for __
gluconeogenesis
The formation and utilization of reserves of triacylglycerol
and glycogen, and the extent to which tissues take up and oxidize glucose, are largely controlled by the hormones ___
insulin and glucagon
– there is either impaired synthesis and secretion of insulin or impaired sensitivity of tissues to insulin action
diabetes mellitus
All the products of digestion are metabolized to a
common product,___, which is then oxidized by the
citric acid cycle
acetyl-CoA
– is the major fuel of most tissues
– most important carbohydrate
– formed by hydrolysis of dietary starch and disaccharides
converted to glucose in the liver
– universal fuel of the fetus
– precursor for synthesis of all the other carbohydrates in the body: Glycogen, ribose and deoxyribose, galactose
Glucose
is metabolized to pyruvate by the pathway of glycolysis
Glucose
Aerobic tissues metabolize pyruvate to acetyl-CoA, which can enter the citric acid cycle for complete oxidation to
CO2 and H2O, linked to the formation of ATP in the process of ____
oxidative phosphorylation
– can also occur anaerobically (in the absence of oxygen) when the end product is lactate.
Glycolysis
an alternative to part of the pathway of glycolysis
pentose phosphate pathway
Triose phosphate intermediates in glycolysis give rise to the ___
glycerol moiety of triacylglycerols
Pyruvate and intermediates of the citric acid cycle provide the carbon skeletons for the synthesis of ____
nonessential or dispensable amino acids
– is the process of synthesizing glucose from noncarbohydrate precursors such as, lactate, amino acids, and glycerol
Gluconeogenesis
Fatty acids may be oxidized to acetyl-CoA (B-oxidation) or esterified with glycerol, forming ___ as the body’s main fuel reserve.
triacylglycerol
Acetyl-CoA formed by β-oxidation of fatty acids may
undergo three fates
- As with acetyl-CoA arising from glycolysis, it is oxidized
to CO2 + H2O via the citric acid cycle. - It is the precursor for synthesis of cholesterol and other
steroids. - In the liver, it is used to form the ketone bodies, acetoacetate and 3-hydroxybutyrate, which are important fuels in prolonged fasting and starvation.
– are required for protein synthesis
– Some must be supplied in the diet since they cannot
be synthesized in the body (essential or indispensable)
amino acids
– remainder of the amino acids; can also be formed from metabolic intermediates by transamination using the amino group from other amino acids
nonessential or dispensable amino acids
After ___, amino nitrogen is excreted as urea, and the carbon skeletons that remain after transamination may
(1) be oxidized to CO2 via the citric acid cycle,
(2) be used to synthesize glucose (gluconeogenesis), or
(3) form ketone bodies or acetyl CoA, which may be oxidized or used for synthesis of fatty acids
deamination
– the nature of the substrates entering and metabolites leaving tissues and organs can be measured
tissue and organ level
– each cell organelle (eg, the mitochondrion) or compartment (eg, the cytosol) has specific roles that form part of a subcellular pattern of metabolic pathways
subcellular level
Amino acids (resulting from the digestion of dietary protein) and glucose (resulting from the digestion of carbohydrates) are absorbed via the \_\_\_\_
hepatic portal vein
– has the role of regulating the blood concentration of these (amino acids and glucose) water soluble metabolites
– also synthesizes the major plasma proteins (eg, albumin)
and deaminates amino acids that are in excess of requirements, synthesizing urea, which is transported to the kidney and excreted
Liver
– glycogen synthesis
Glycogenesis
– fatty acid synthesis
Lipogenesis
- utilizes glucose as a fuel, both aerobically, forming CO2, and anaerobically, forming lactate
- stores glycogen as a fuel for use in muscle contraction and synthesizes muscle protein from plasma amino acids
Skeletal muscle
– are mainly triacylglycerol, and are hydrolyzed to monoacylglycerols and fatty acids in the gut, then reesterified in the intestinal mucosa
Lipids
- the largest of the plasma lipoproteins
- -also contain lipid-soluble nutrients, including vitamins A, D, E, and K
- is not taken up directly by the liver
- It is first metabolized by tissues that have lipoprotein lipase
chylomicrons
- hydrolyzes the triacylglycerol (chylomicrons)
- - releasing fatty acids that are incorporated into tissue lipids or oxidized as fuel
lipoprotein lipase
- is the main fuel reserve of the body
- It is hydrolyzed (lipolysis) and glycerol and nonesterified
(free) fatty acids are released into the circulation
- It is hydrolyzed (lipolysis) and glycerol and nonesterified
Adipose tissue triacylglycerol
In the liver, newly synthesized triacylglycerol and triacylglycerol from chylomicron remnants is secreted into the circulation in __
very low density lipoprotein (VLDL)
Partial oxidation of fatty acids in the liver leads to __
ketone body production (ketogenesis)
- acts as the focus of carbohydrate, lipid, and amino acid metabolism
- contains the enzymes of the citric acid cycle, β-oxidation of fatty acids and ketogenesis, as well as the respiratory chain and ATP synthase
mitochondrion
a precursor for the synthesis of glucose in the cytosol
oxaloacetate
– contain the enzyme system for triacylglycerol synthesis
membranes of the endoplasmic reticulum
Regulation of the overall flux through a pathway is achieved by control of one or more key reactions in the pathway, catalyzed by ___
regulatory enzymes
- first reaction in a pathway that is saturated with the substrate
- can be identified as a nonequilibrium reaction in which the Km of the enzyme is considerably lower than the normal concentration of substrate
flux-generating reaction
Enzymes catalyzing nonequilibrium reactions are
often ____ subject to the rapid actions of “feedback” or “feed-forward” control by allosteric modifiers, in immediate response to the needs of the cell.
allosteric proteins
True or False
Fatty acids (and ketone bodies formed from them) cannot be used for the synthesis of glucose
True
True or False
Acetyl-CoA (and any substrates that yield acetyl-CoA) can be used for gluconeogenesis.
False
It can never be used for gluconeogenesis.
Most of the amino acids in excess of requirements for protein synthesis (arising from the diet or from tissue protein turnover) yield pyruvate, or four- and five-carbon intermediates of the citric acid cycle. These amino acids are classified as \_\_\_
glucogenic
– two amino acids that yield only acetyl-CoA on oxidation, and hence cannot be used for gluconeogenesis
lysine and leucine
– amino acids that give rise to both acetyl-CoA and intermediates that can be used for gluconeogenesis
phenylalanine, tyrosine, tryptophan, and isoleucine
Those amino acids that give rise to acetyl-CoA are referred to as ___, because in prolonged fasting and starvation much of the acetyl-CoA is used for synthesis of ketone bodies in the liver.
ketogenic
Glucose uptake into muscle and adipose tissue is controlled by __, which is secreted by the β-islet cells of the pancreas in response to an increased concentration of glucose in the portal blood.
insulin
In the fasting state, the glucose transporter of muscle
and adipose tissue ___ is in intracellular vesicles.
GLUT-4
The increase in secretion of ___ by α cells of
the pancreas inhibits glycogen synthetase, and activates glycogen phosphorylase in the liver
glucagon
- cannot contribute directly to plasma glucose, since muscle lacks glucose-6-phosphatase, and the
- -primary use is to provide a source of glucose-6-phosphate for energy-yielding metabolism in the muscle itself.
Muscle glycogen
___ with a high Km, so that as the concentration of glucose
entering the liver increases, so does the rate of synthesis of
glucose-6-phosphate
isoenzyme of hexokinase (glucokinase)
as fasting is prolonged, the plasma concentration of ___ increases markedly
ketone bodies (acetoacetate and 3-hydroxybutyrate)
acetyl-CoA formed by oxidation of fatty acids in muscle inhibits pyruvate dehydrogenase, leading to an ___
accumulation of pyruvate
substrate for gluconeogenesis in the liver
glycerol
In patients with ___ as a result of release of cytokines in response to tumors and disease, there is an increase in the rate of tissue protein catabolism, as well as a considerably increased metabolic rate, so they are in a state of advanced starvation.
cachexia
is the study of the roles of sugars in health and disease.
Glycobiology
is the entire complement of sugars of an organism, whether free or present in more complex molecules
glycome
– the comprehensive study of glycomes, including genetic, physiological, pathological, and other aspects
Glycomics
Classification of Carbohydrates
- Monosaccharides
- Disaccharides
- Oligosaccharides
- Polusaccharides
- metabolic intermediates in glycolysis and the pentose phosphate pathway (hexose monophosphate shunt)
- Pentoses - important in nucleotides, nucleic acids, and several coenzymes
- Glucose, galactose, fructose, and mannose - physiologically the most important hexoses
Monosaccharides
- a molecule in which a sugar is bound to another functional group via a glycosidic bond
- O-glycosidic bond
- N-glycosidic bond
- Exmples: salicin, cardiac glycosides, Ouabain, streptomycin
Glycosides
– sugars in which one hydroxyl group has been replaced by hydrogen
– Examples
Deoxyribose - derived from the sugar ribose by loss of an oxygen atom
l-fucose - Cosmetics, pharmaceuticals, dietary supplements
2-deoxyglucose - Competitively inhibits G6 PO4
Deoxy Sugars
– Components of Glycoproteins, Gangliosides and Glycosaminoglycans
– Examples
d-glucosamine - constituent of hyaluronic acid (water holding/filler)
d-galactosamine - Chondrosamine (cartilage)
d-mannosamine
– Clinical Importance: antibiotics (eg, erythromycin)
Amino Sugars (Hexosamines)
– sugars composed of two monosaccharide residues linked by a glycoside bond
Maltose - Glucose and glucose
Sucrose - glucose and fructose
Lactose - Glucose and galactose
Disaccharides
- are condensation products of three to ten monosaccharides
- Most are not digested by human enzymes.
Oligosaccharides
– are condensation products of more than ten monosaccharide units
– examples are the starches and dextrins, which may be linear or branched polymers
– are sometimes classified as hexosans or pentosans, depending on the constituent monosaccharides
(hexoses and pentoses, respectively)
Polysaccharides
- foods contain a wide variety of other polysaccharides that are collectively known as ___;
- they are not digested by human enzymes, and are the major component of dietary fiber.
- -Examples are cellulose from plant cell walls (a glucose polymer; and inulin, the storage carbohydrate in some plants (a fructose polymer).
nonstarch polysaccharides
– a homopolymer of glucose forming an α-glucosidic chain, called a glucosan or glucan
– the most important dietary carbohydrate in cereals, potatoes, legumes, and other vegetables
– two main constituents:
Amylose (13%-20%)
Amylopectin (80%-87%)
Starch
- 24 to 30 glucose residues
- α1 → 4 linkages in the chains
- α1 → 6 linkages at the branch points
Amylopectin (80%-87%)
– measure of its digestibility
– based on the extent to which it raises the blood concentration of glucose
– ranges from 1 (or 100) to 0 for those that are not hydrolysed at all
55 or less = Low (good)
56- 69 = Medium
70 or higher = High (bad)
glycemic index
- animal starch
- storage polysaccharide
- more highly branched structure than amylopectin
- Muscle glycogen
- contain up to 60,000 glucose residues
Glycogen
- polysaccharide of fructose found in tubers and roots of dahlias, artichokes, and dandelions
- readily soluble in water
- used to determine the glomerular filtration rate no nutritional value
Inulin
- chief constituent of plant cell walls
- Insoluble
- Consists of β-d-glucopyranose units linked by β1 → 4 bonds
- an important source of “bulk” in the diet
- major component of dietary fiber
Cellulose
- structural polysaccharide in the exoskeleton of crustaceans and insects
- N-acetyl-d-glucosamine units joined by β1 → 4 glycosidic bonds
Chitin
- occurs in fruits
- - a polymer of galacturonic acid linked α-1→ 4
Pectin
- Aka mucopolysaccharides
- Contains amino sugars and uronic acids
- Proteoglycan - attached to a protein molecule; substance of connective tissue (Hold water occupy space)
- Examples: hyaluronic acid, chondroitin sulfate, and heparin
Glycosaminoglycans
- Aka Mucoproteins
- Proteins containing branched or unbranched oligosaccharide chains
- occur in cell membranes
- Glycosylation
- 5% of the weight of cell membranes
Glycoproteins
Biomedical Importance of Lipids
– fats, oils, steroids, waxes
– Common Physical proprties - Relatively insoluble in water: soluble in nonpolar solvents
– important dietary constituents: fat-soluble vitamins; Micronutrients; long chain omega-3 fatty acids
– stored in adipose tissue
– thermal insulator
– Myelin sheaths
– Lipoprotein
Clinical Diseases
obesity, diabetes mellitus, and atherosclerosis
– are a heterogeneous group of compounds, including
fats, oils, steroids, waxes, and related compounds, that are
related more by their physical than by their chemical properties
lipids
Fat is stored in ___, where it also serves as a thermal insulator in the subcutaneous tissues and around certain organs.
adipose tissue
Nonpolar lipids act as ___, allowing rapid propagation of depolarization waves along myelinated nerves
electrical insulators
Classification of Lipids
- Simple Lipids
- Complex Lipids
- Precursor or Derived Lipids
___ include fats and waxes which are esters of fatty acids with various alcohols
Simple lipids
Groups of Simple Lipids
- Fats – Esters of fatty acids with glycerol. Oils are fats in the liquid state.
- Waxes – Do not have triglyceride ester of three fatty acids; Fatty acid and alcohol esters
- - Esters of fatty acids with higher molecular weight monohydric alcohols.
Groups of Complex Lipids
- Phospholipids
- Glycolipids (glycosphingolipids)
- Other complex lipids
– Lipids containing, in addition to fatty acids and an alcohol, a phosphoric acid residue
– frequently have nitrogen-containing bases (eg, choline)
and other substituents
Phospholipids
– Lipids containing a fatty acid, sphingosine, and carbohydrate
Glycolipids (glycosphingolipids)
- Lipids such as sulfolipids and amino lipids
- - Lipoproteins may also be placed in this category.
Other complex lipids:
– group of glycolipids which include fatty acids, glycerol, steroids, other alcohols, fatty aldehydes, ketone bodies, hydrocarbons, lipid-soluble vitamins and micronutrients, and hormones
Precursor and derived lipids
– acylglycerols (glycerides), cholesterol, and cholesteryl esters are termed ___ because they are uncharged
neutral lipids
Fatty Acids Are Aliphatic Carboxylic Acids
free fatty acids – transport form in the plasma
Saturated – containing no double bonds
Unsaturated – containing one or more double bonds
Nomenclature
– systematic nomenclature names the fatty acid after the hydrocarbon with the same number and arrangement
of carbon atoms, with -oic being substituted for the final -e
– saturated acids end in -anoic
– unsaturated acids with double bonds end in -enoic
Nomenclature (Powerpoint)
- Palmitic – C16:0 or 16:0
- - #C : # double bonds - Linoleic – C18:2 (9,12)
- - 18 Ϫ9,12
- - ώ-carbon (methyl carbon)
- - Ώ-6 family (18-12) - Linolenic Acid – C18:3 (9,12,15) or 18 Ϫ9,12,15
Are there essential lipids?
Linoleic and linolenic acid (ADEK)
Are there essential amino acids?
- Adults: 9
- - Infants: 10 (arginine)
Are there essential carbohydrates?
NO
- Contain No Double Bonds
- - based on acetic acid (CH3—COOH)
Saturated Fatty Acids
Unsaturated fatty acids may be further subdivided as follows:
- Monounsaturated (monoethenoid, monoenoic) – acids,
containing one double bond. - Polyunsaturated (polyethenoid, polyenoic) – acids, containing two or more double bonds.
- Eicosanoids – These compounds, derived from eicosa
(20-carbon) polyenoic fatty acids, comprise
the prostanoids, leukotrienes (LTs), and lipoxins (LXs).
– exist in virtually every mammalian tissue, acting as local hormones; they have important physiologic
and pharmacologic activities.
– They are synthesized in vivo by cyclization of the center of the carbon chain of 20-carbon (eicosanoic) polyunsaturated fatty acids (eg, arachidonic acid) to form a cyclopentane ring
Prostaglandins
– have the cyclopentane ring interrupted with an oxygen atom (oxane ring)
thromboxanes
- are a third group of eicosanoid derivatives formed via the lipoxygenase pathway
- are characterized by the presence of three or four conjugated double bonds
leukotrienes and lipoxins
Geometric Isomerism
cis-
- If the acyl chains are on the same side of the bond
- i.e oleic acid
Trans-
- If the acyl chains are on opposite sides
- i.e. elaidic acid
Most Naturally occurring Unsaturated Fatty Acids
– Double bonds in fatty acids are in the cis-configuration
– Trans-double bonds are unnatural
Margarine, etc
Decrease liquid fluidity
– Trans fatty acids and saturated fatty acids are associated with an increased risk of atherosclerosis
– are present in certain foods, arising as a by-product of the saturation of fatty acids during hydrogenation, or “hardening,” of natural oils in the manufacture of margarine.
Trans fatty acids
True or False
Most Naturally Occurring Unsaturated Fatty Acids Have cis Double Bonds
True
Physical and Physiologic Properties of Fatty Acids
- Reflect Chain Length and Degree of Unsaturation
- More saturated - More solid at body temperature
- Polyunsaturated - Liquid to below zero dec celsius; membrane lipids; Hibernators
Omega 3 Fatty Acids
α-linolenic (ALA) - Found in plant oils
eicosapentaenoic (EPA) - found in fish oil
docosahexaenoic (DHA) - found in fish and algal oils
- anti-inflammatory effects perhaps due to promoting the synthesis of less inflammatory prostaglandins and leukotrienes compared to omega 6
- are beneficial, particularly for cardiovascular disease, but also for other chronic degenerative diseases such as cancer, rheumatoid arthritis, and Alzheimer disease.
Omega 3 Fatty Acids
- Main storage forms of fatty acids
- - carbons 1 and 3 of glycerol are not identical when viewed in three dimensions
Triacylglycerols (Triglycerides)
– Many phospholipids are derivatives of ___, in which the phosphate is esterified with one OH group of glycerol and the other two OH groups are esterified to two long chain fatty acids (glycerophospholipids).
phosphatidic acid
__ containing choline, (phosphatidylcholines, commonly called lecithins) are the most abundant phospholipids of the cell membrane and represent a large proportion of the body’s store of choline.
Glycerophospholipids
has two long chain hydrocarbon tails
Phospholipids
is important in nervous transmission, as acetylcholine, and
as a store of labile methyl groups
Choline
– is a very effective surface-active agent and a major constituent of the surfactant preventing adherence, due to surface tension, of the inner surfaces of the lungs
Dipalmitoyl lecithin
absence of Dipalmitoyl lecithin from the lungs of premature infants causes __
respiratory distress syndrome
- Ethanolamine or serine, respectively, replaces choline
- - plays a role in apoptosis (programmed cell death)
Phosphatidylethanolamine (cephalin) and phosphatidylserine
– are found in the outer leaflet of the cell membrane lipid bilayer and are particularly abundant in specialized
areas of the plasma membrane known as lipid rafts
– are also found in large quantities in the myelin sheath that surrounds nerve fibers
– are believed to play a role in cell signaling and in apoptosis
– contain no glycerol, and on hydrolysis they yield a fatty acid, phosphoric acid, choline, and sphingosine
Sphingomyelins
The combination of sphingosine plus fatty acid is known as
__, a structure also found in the glycosphingolipids
ceramide
- Give rise to cardiolipin
- Found only in mitochondria
- Alterations in function or decreased levels associated in heart failure and hypothyroidism and aging
Phosphatidylglycerol
- important in the metabolism and interconversion of phospholipids
- found in oxidized lipoproteins and has been implicated in some of their effects in promoting
lysophosphatidylcholine (Lysolecithin)
– are lipids with an attached carbohydrate or carbohydrate
chain
– are widely distributed in every tissue of the body, particularly in nervous tissue such as brain
– occur particularly in the outer leaflet of the plasma membrane, where they contribute to cell surface carbohydrates which form the glycocalyx
Glycolipids (Glycosphingolipids)
- major glycosphingolipid of brain and other nervous tissue
- Converted to sulfatide (present in high amounts in myelin)
Galactosylceramide
- resembles galactosylceramide
- head group is glucose rather than galactose
- predominant simple glycosphingolipid of extraneural tissues
Glucosylceramide
– complex glycosphingolipids derived from glucosylceramide
– Function in cell-cell recognition and communication and as receptors for hormones and bacterial toxins (cholera)
GM1
Gangliosides
- Precursor is cholesterol
- Bile Acids
- Adrenocortical hormones
- Sex hormones
- Vitamin D
- Cardiac glycosides
Steroids
– is a Precursor of Vitamin D
Ergosterol
- not steroids
- related because they are synthesized, like cholesterol from fivecarbon isoprene units
- rubber, camphor, the fat-soluble vitamins A, D, E, and K, and β-carotene (provitamin A)
- Ubiquinone - Respiratory chain in mitochondria
- Dolichol - takes part in glycoprotein synthesis
Polyprenoids
auto-oxidation of lipids
- -responsible for rancidity of foods
- damage to tissues in vivo
- -cancer, inflammatory diseases, atherosclerosis, and aging
free radicals
- molecules that have unpaired valence electrons
- reactive oxygen species (ROS)
- -Chain reaction providing continuous supply of ROS: Initiation; Propagation and Termination
Lipid Peroxidation
To control and reduce lipid peroxidation, both humans in
their activities and nature invoke the use of ___
antioxidants
2 classes of antioxidant
- preventive antioxidants – reduce the rate of chain initiation
- - eg Catalase; EDTA; DTPA; Glutathione peroxidase - chain-breaking antioxidants – interfere with chain propagation
- - eg Superoxide dismutase; vitamin E
- a part of the molecule is hydrophobic, or water insoluble; and a part is hydrophilic, or water soluble
- Basic structure in biologic membranes
- Micelles
- liposomes
Amphipathic
– Aka Tricarboxylic Acid Cycle (TCA) or Krebs Cycle
– Final common pathway for the aerobic oxidation of
Carbohydrates, Fatty Acids, and Proteins
– Occurs in most tissues but most significantly happens in
the Liver
– Reactions and Enzymes are found in the mitochondrial
matrix, except succinate dehydrogenase (inner
membrane)
Citric Acid Cycle
Functions of Citric Acid Cycle
- Provides majority of ATP for energy
- Interconverts amino acids (transaminationdeamination)»creates amino acids or destroys amino acids (producing glucose)
- Has a crucial role in fatty acid synthesis
Substrates and Product of Krebs Cycle (Citric Acid Cycle)
Substrates: Acetyl CoA and Oxaloacetate Products: 12 ATP(from 3 NADH, 1 FADH, 1 GTP), 2CO2, H2O, heat -- It’s a cycle! -- Oxaloacetate will be regenerated
Steps of Citric Acid Cycle
“Cindy Is Kind So She Forgives More Often” C itrate I socitrate alpha K etoglutarate S uccinyl CoA S uccinate F umarate M alate O xaloacetate
Mnemonic: (Krebs Cycle)
F – 6 (FADH - Fumarate) A – 5 (ATP - Succinate) N – 3, 4, 8 (NADH - Alpha Ketoglutarate, Succinyl Coa and Malate) All the rest, water CO2 – 3,4
Take Note (Krebs Cycle)
- A-ketoglutarate dehydrogenase complex->requires 5 B
vitamins - Steps produce ATP uses oxidative phosphorylation
mainly except for the synthesis of Succinate - Gluconeogenic sites (liver, kidney) produce GTP, nongluconeogenic
sites produce ATP - GTP is used in the gluconeogenic step
oxaloacetate->PEP
ATP Yield from TCA: Acetyl-CoA
ATPs from substrate level phosphorylation: 1
ATPs from NADH: 9
ATPs from FADH2: 2
TOTAL ATP YIELD: 12
ATP Yield from TCA: Pyruvate
ATPs from substrate level phosphorylation: 1
ATPs from NADH: 12
ATPs from FADH2: 2
TOTAL ATP YIELD: 15
Role in Transamination-Deamination Amino Acids
- Amino acids may be used to create TCA intermediates
(and ultimately glucose) or TCA cycles maybe used to
create amino acids - Transamination Reactions: TCA intermediates->amino acids
- Deamination Reactions: amino acids->TCA intermediates
Role in Fatty Acid Synthesis
- TCA Intermediate Citrate transports Acetyl CoA from
the mitochondrial matrix and into the cytoplasm to
initiate fatty acid synthesis (Citrate Shuttle)
Other Functions (Kreb’s Cycle)
- Succinyl CoA can be used for heme synthesis and to
activate ketone bodies in extrahepatic tissues - Malate can be used for gluconeogenesis
Regulatory Mechanisms
- Krebs Cycle is active in both the well-fed state and
fasting state - No hormonal control
- No new synthesis of oxaloacetate
- Regulatory mechanisms are not fully known
Regulatory Mechanisms- Suspected Mechanisms:
- Pyruvate Dehydrogenase
- Allosteric Inhibition of Citrate Synthase by ATP and long-chain fatty Acyl CoA
- Allosteric Activation of mitochondrial NADdependent
IDH - Inhibition of Succinate dehydrogenase by oxaloacetate
- Concentration of oxaloacetate
Inhibitors of the Citric Acid Cycle
- Fluoroacetate - inhibit conversion of citrate to cis-aconitate
- Arsenite - inhibit alpha ketoglutarate to succinyl coa
- Malonate - inhibit conversion of succinate to fumarate
- Major pathway for glucose metabolism (but also for
galactose and fructose) - Made up of 10 Steps
- Can work with or without oxygen
Glycolysis
Glycolysis
- Substrate: mainly Glucose
- Product: Pyruvate or Lactate
- Overall Reaction: Glucose + 2 ADP + 2Pi 2 Lactate or
Pyruvate + 2 ATP + 2 H2O - Occurs in the cytoplasm of all cells
Glucose Transporters (GLUTs)
GLUT – 1 -Erythrocytes, BBB, kidney, colon, placenta
Function: Uptake of glucose
GLUT – 2 - Liver, pancreatic B cell, small intestine, kidney
Function: Rapid uptake and release of glucose
GLUT – 3 - Brain(Neurons), kidney, placenta
Function: Uptake of glucose
GLUT – 4 - Heart and skeletal muscle, adipose tissue
Function: Insulin stimulated uptake of glucose
GLUT – 5 - Small intestine
Function: Absorption of Fructose at the luminal side of the SI
Types of Glycolysis
- Anerobic Glycolysis
In cells without a mitochondria (e.g. RBCs) or anoxic cells
(e.g. white muscle)
Final product: Lactate - Aerobic Glycolysis
In cells with a mitochondria and adequate supply of oxygen
Final Product: Pyruvate
2 Stages of Glycolysis
- Energy Investment Phase - uses ATP
- Phosphorylated forms of intermediates are synthesized at
the expense of ATP - Energy Generation Phase - produce ATP
- 2 molecules of ATP are formed by substrate level
phosphorylation
Irreversible Steps in Glycolysis
- Phosphorylation of glucose
- Phosphorylation of fructose 6-phosphate – Rate-limiting
step of Glycolysis - Formation of pyruvate
- Present in most tissues
- Can phosphorylate glucose, fructose, galactose
- Inhibited allosterically by Glucose 6P
- Low Km
- High affinity for glucose
- Low Vmax
Hexokinase
- Present in liver parenchymal cells (to initiate FA synthesis, glyconesis), islet cells of the pancreas (to initiate insulin secretion)
- Phosphorylate glucose alone
- Inhibited by Fructose 6P
- High Km
- Low affinity for glucose
- High Vmax
- Liver activity stimulated by insulin
Glucokinase
Fructose 6P->Fructose 1,6BP
- Enzyme: phosphofructokinase-1 (PFK-1)
- Irreversible and rate-limiting step of glycolysis
- PFK-1 is different from PFK-2!
Phosphofructokinases
1. PFK-1 Converts Fructose 6P to Fructose 1,6BP Inhibited by ATP and citrate Activated by Fructose 2,6 Bisphosphate (most potent; via allosteric activation) and AMP
- PFK-2
Converts Fructose 6P to Fructose 2,6BP
Inhibited by ↓insulin, ↑glucagon (starvation)
Activated by ↑insulin, ↓glucagon (well fed)
PEP->Pyruvate
- Substrate-level phosphorylation to yield 1 ATP per
molecule of phosphoenolpyruvate - Enzyme: Pyruvate Kinase
Activated by Fructose 1,6BP
Inhibited by phosphorylation, which occurs when ↑glucagon,
↑cAMP
Steps involved in the Production of ATP
Glycolysis
- 1,3-bisphosphoglycerate->3-phosphoglycerate
Enzyme: phosphoglycerate kinase - PEP->pyruvate
Enzyme: pyruvate kinase
- The most common enzyme defect in glycolysis
- Manifests as chronic hemolytic anemia
- Aldolase A deficiency may also cause hemolytic anemia
Pyruvate Kinase Deficiency
Patients have low exercise capacity, particularly on high
carbohydrate diets
Muscle Phosphofructokinase Deficiency
Role of NADH in Glycolysis
- Oxidation of glyceraldehyde 3 phosphate->1,3
bisphosphoglycerate
Enzyme: glyceraldehyde 3 phosphate dehydrogenase - 2 Possible Fates
1. Can enter the malate-aspartate or G3P shuttle and be
converted to ATP
2. Can be used to convert pyruvate to lactateAerobic
Glycolysis: NADH converted to ATP;
transported using shuttles:
- Malate Aspartate Shuttle
yields 3 ATPs each
liver, kidney and heart - Glycerol Phosphate Shuttle
yields 2 ATPs each
skeletal muscle and brain
Anaerobic Glycolysis:
Pyruvate is converted to lactate by the action of Lactate Dehydrogenase
Synthesis of 2,3 BPG
- In RBCs, the reaction catalyzed by phosphoglycerate
kinase is bypassed - 1,3-bisphosphoglycerate is converted to 2,3-
bisphosphoglycerate or 2,3 BPG - Enzyme: Bisphosphoglycerate Mutase
- Function: binds to HgB and causes a shift to the R of the
Hemoglobin-O2 dissociation curve - Chronic hypoxia->reactive polycythemia->inc BPG
mutase->inc 2,3 BPG->shift to the R
Pyruvate to Acetyl Coa
- This step is NOT strictly part of Glycolysis
- Happens in the mitochondria
- Enzyme: Pyruvate Dehydrogenase (PDH) complex
- Also produces NADH and CO2
- Regulation is of 2 Forms:
1. End-Product Inhibition
2. Regulation by interconversion of active and
inactive forms - Activated by: NAD+, CoA and pyruvate
- Inhibited by: ATP, Acetyl-CoA and NADH
Pyruvate to Acetyl Coa - Co-enzymes:
- Thiamine pyrophosphate
- FAD
- NAD+
- Coenzyme A (contains pantothenic acid)
- Lipoic acid
- most common biochemical cause of congenital lactic acidosis
- X-linked dominant
- Brain is deprived of Acetyl-CoA: psychomotor retardation
and death - Treatment: ketogenic diet
Pyruvate Dehydrogenase Deficiency
- inactivates pyruvate dehydrogenase by binding to lipoic acid
- Aside from inhibiting pyruvate dehydrogenase, pentavalent aresenic (arsenate) also competes with inorganic phosphate as a substrate for glyceraldehyde 3P dehydrogenase
Arsenic Poisoning
Chronic alcoholics are prone to thiamine-deficiency and may develop potentially fatal pyruvic and lactic acidosis
Chronic alcoholism
Fates of Pyruvate
- Lactate (Lactate dehydrogenase) - Anaerobic
- Ethanol (Pyruvate decarboxylase) - Yeast and certain microorganisms
- Acetyl Coa (Pyruvate dehydrogenase) - Aerobic
- Oxaloacetate (Pyruvate carboxylase) - final step in gluconeogenesis
ATP Yield of Glycolysis
Anaerobic: 4
Aerobic: 4
- Aka“Hexose Monophosphate Shunt”
- Happens in the well-fed state
- An alternative pathway for the metabolism of glucose
- No ATP is used or produced
Pentose Phosphate Pathway
Pentose Phosphate Pathway: What is it for?
Produces NADPH (NOT NADH!) which is required for: fatty acid and steroid biosynthesis, glutathione reduction inside RBCs, cytochrome P450, respiratory burst of WBCs, and synthesis of nitric oxide
Produces Ribose 5-phosphate required for biosynthesis of nucleotides
Function of NADPH
- Lipid Synthesis
- Create antioxidant form of glutathione
- Create Oxygen Free radicals to kill bacteria
Pentose Phosphate Pathway: Where does it occur?
In the cytoplasm
it is required for synthesis of DNA and RNA (which is made up of nucleotides)
Ribose 5-phosphate
Pentose Phosphate Pathway: What are the substrates?
Glucose-6-P
No consumption or production of ATP
Pentose Phosphate Pathway: What are the products?
ribose-5-P, fructose-6-P, and glyceraldehyde-3-P
NADPH
Pentose Phosphate Pathway: Which step is rate-limiting?
Reaction: glucose-6-P –> 6-phosphogluconate
Enzyme: glucose-6-P dehydrogenase
Pentose Phosphate Pathway: ACTIVE in the ff sites
Liver Adipose tissue Adrenals, thyroid and testes RBC LACTATING mammaries
Pentose Phosphate Pathway: LOW in the ff sites
Skeletal muscle
NON-LACTATING mammaries
Pentose Phosphate Pathway: Two Phases in Pathway
Phase 1: Oxidative (Irreversible)
Enzyme: Glucose-6-Phosphate dehydrogenase
Products: NADPH; Ribulose-5-P
Phase 2: Non-Oxidative (Reversible)
Enzyme: Transketolase - refers to several enzymes
Product: Ribose-5-Phosphate
cofactor of transketolase for it to work
Thiamine
Pentose Phosphate Pathway
- Complete PPP (Oxidative and Non-Oxidative)
for those organs that need both NADPH and ribose 5-P - Incomplete PPP (Non-oxidative phase Only)
for all organs requiring ribose-5-P only
Pentose Phosphate Pathway: Important Points:
At the start of the reaction – Glucose 6-phosphate
At the end of the reaction – Glucose 6-phosphate
Rate-Limiting Enzyme: G6PD (NOT G6P!)
- transfers two carbon unit of a ketose onto the aldehyde carbon of an aldose sugar
- Co-factors: Mg2+ and Vitamin B1 (Thiamine)
Transketolase enzyme
- reduced glutathione (G-SH) removes H2O2 in a reaction catalyzed by glutathione peroxidase
- reacting with H2O2 oxidizes glutathione (G-S-S-G) but only ONLY REDUCED glutathione can remove H2O2
- very important in RBCs
Glutathione
- Most common disease producing enzyme abnormality in humans
- Involves in NADPH in RBCs and activity of glutathione reductase causing free radicals and peroxides accumulate
- Hemolytic anemia due to poor RBC defense against oxidizing agents
- Precipitating factors: anything that causes oxidative stress
most common: infection
drugs (sulfonamides, primaquine, chloramphenicol)
fava beans - Neonatal jaundice: 1 to 4 days after birth
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
altered hemoglobin that precipitates within RBCs; irregular precipitates of denatured Hgb
Heinz bodies
altered RBCs due to phagocytic removal of Heinz bodies in spleen
Bite Cells
- Deficiency in NADPH oxidase
- converts molecular oxygen into superoxide in leukocytes (especially neutrophils and macrophages) and used in the respiratory burst that kills bacteria
- Severe, persistent and chronic pyogenic infections caused by catalase-positive bacteria
Chronic Granulomatous Disease
- Another alternative pathway for glucose
- Zero ATP is used or produced
- Cellular site: cytoplasm
- Organ site: Liver
Uronic Acid Pathway
- At the start of the reaction: glucose 6-phosphate
- At the end of the reaction: glucoronic acid, ascorbic acid (EXCEPT humans and other species) and pentoses
- Uses of Glucoronic acid
- Product: Glucoronic Acid
Uronic Acid Pathway
- Deficiency of reductase enzyme needed to convert L-xylulose to xylitol
- Accumulation of L-xylulose will lead to increase levels in the urine
Essential Pentosuria
cofactor of Glutathione Peroxidase
Selenium
Fructose Metabolism
- Fructose is an Isomer of glucose
- Fructose and Galactose: converted into Glycolytic Intermediates
- Fructokinase is unaffected by fasting or insulin
- Cellular site: Cytoplasm
- Organ site: mainly in the Liver
but also in kidney, intestines, adipose tissue, muscle, semen
- As part of synthesis of proteoglycans
- For reactions of substrates such as steroid hormones, bilirubin, drugs excreted in the urine or bile as glucoronid conjugate
Glucoronic Acid
- Rapid glycolysis in the liver - NOT limited by PFK
- More efficient and higher energy yield - Bypasses the energy investment phase of glycolysis
- Flood the pathways in the liver leading to an increase in the following: Fatty acid synthesis; Esterification of fatty acids and Increased VLDL secretion
Fructose Metabolism
2 ALDOLASES
aldolase A and aldolase B
1. Aldolase A: for glycolysis
fructose-1,6-BP -> DHAP + glycerol-3-P
- Aldolase B: for fructose metab
fructose-1-P -> DHAP + glyceraldehyde
Fructose Metabolism
- Phosphorylation of fructose
fructose -> fructose-1-P
Enzyme: fructokinase or hexokinase - Formation of DHAP and Glyceraldehyde
fructose-1-P -> dihydroxyacetone phosphate (DHAP) + glyceraldehyde
Enzyme: aldolase B
- defect in fructokinase
- benign and asymptomatic whose only symptom is the appearance of fructose in blood and urine
Essential Fructosuria or fructokinase deficiency
- autosomal recessive deficiency of aldolase B
- fructose 1-P, fructose 1,6 BP accumulates leading to increase phosphate and allosterically inhibiting liver glycogen phosphorylase resulting in decrease glycogenolysis and decrease gluconeogenesis
- Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting
- Treatment: avoid intake of fructose and sucrose
Fructose Intolerance or Aldolase B Deficiency
- Mannose is an important component of glycoproteins
- Very little contribution from diet
- Isomerization between mannose and fructose
mannose-6-P -> fructose-6-P
Enzyme: phosphomannose isomerase
Mannose Metabolism
- Enzyme: aldose reductase
- Found in lens, retina, Schwann cells, liver, kidney, placenta, RBC, ovaries, seminal vesicles
Glucose -> Sorbitol
- Enzyme: sorbitol dehydrogenase
- Found in the seminal vesicles since fructose is the fuel of sperm
Sorbitol -> Fructose
- In DM, since there is SO MUCH GLUCOSE, equilibrium favors the formation of MORE SORBITOL.
- But, the lens and nerves lack sorbitol dehydrogenase. Sorbitol accumulates in these tissues and attract water by osmosis.
lens: formation of cataracts
nerves: peripheral neuropathy
Sorbitol Metabolism
- also an isomer of glucose
- Cellular site: cytoplasm
- Organ sites: mainly in the liver, but also in many extrahepatic tissues such as the mammary gland
- Needed to create the following:
1. Lactose (for milk production)
2. As a constituent of glycolipids (cerebrosides, proteoglycans, glycoproteins)
Galactose Metabolism
Galactose Metabolism
- Phosphorylation of galactose
galactose -> galactose-1-P
Enzyme: galactokinase or hexokinase - Formation of UDP-galactose
galactose-1-P + UDP-glucose ->UDP-galactose + glucose-1-P
(UDP-galactose is the activated form of galactose)
Enzyme: galactose-1-P uridyl transferase
-Use of galactose as carbon source
UDP-galactose -> UDP-glucose
Enzyme: UPD-hexose-4-epimerase
- causes galactosemia and galactosuria
- cataracts in early childhood
- treatment: eliminate sources of galactose from the diet
Galactokinase Deficiency
- autosomal recessive condition of absence of galactose-1-P uridyltransferase
- cataracts within a few days of birth
- galactitol accumulates in the presence of galactose and lactose in the diet causing cataracts + hepatosplenomegaly + mental retardation
Classic Galactosemia or Galactose-1-P Uridyltransferase Deficiency
are a group of inherited disorders characterized by deficient mobilization of glycogen or deposition of abnormal forms of glycogen, leading to liver damage and muscle weakness; some glycogen storage diseases result in early death
Glycogen storage diseases
The initial steps in glycogen synthesis involve the protein ___, a 37-kDa protein that is glucosylated on a specific
tyrosine residue by UDPGlc
– catalyzes the transfer of a further seven glucose residues from UDPGlc, in 1 → 4 linkage, to form a glycogen primer that is the substrate for glycogen synthase.
glycogenin
– catalyzes the formation of a glycoside bond between C-1 of the glucose of UDPGlc and C-4 of a terminal glucose residue of glycogen, liberating uridine diphosphate (UDP).
Glycogen synthase
When a growing chain is at least 11 glucose residues long,
branching enzyme transfers a part of the 1 → 4-chain (at
least six glucose residues) to a neighboring chain to form a
1 → 6 linkage, establishing a ___.
branch point
Production of glucose from the following intermediates
- intermediates of glycolysis and the TCA
- glycerol from triacylglycerols
- lactate through the Cori Cycle
- carbon skeletons (alpa-ketoacids) of glycogenic amino acids
Gluconeogenesis
Gluconeogenesis: Where does it occur?
- Occurs in the liver (90%) and the kidney (10%)
- During prolonged fasting, the kidneys contribute as much as 40%
- Occurs in both mitochondria and cytoplasm
Gluconeogenesis: What is the substrate and product?
Substrate: Pyruvate
Product: Glucose
Which step is rate-limiting?
Reaction: Fructose 1,6-biphosphate -> Fructose 6-Phosphate
Enzyme: Fructose 1,6-biphosphatase
- another substrate of gluconeogenesis
Glycerol
- enters main gluconeogenic pathway via citric acid cycle after conversion of succinyl Coa
- a major precursor of glucose in ruminants
Propionate
Gluconeogenesis
Step 10: Pyruvate -> OAA -> PEP
Enzymes: Pyruvate Carboxylase
KEEP IN MIND
CARBOXYLASES attach a carbon atom using CO2 as a substrate. ALL carboxylases require BIOTIN as a co-factor.
Gluconeogenesis
Step 3: Fructose-1,6-BP -> Fructose-6-P
This is the rate-limiting step of gluconeogenesis
Enzyme: fructose-1,6-bisphosphatase
Activator: ATP
Inhibitor: Fructose-2,6-BP and AMP
Fructose-2,6-BP - promotes glycolysis and inhibits gluconeogenesis
Gluconeogenesis
Step 1: Glucose-6-P -> Glucose
- Final step, which is shared with glycogen degradation
- End goal: releases free glucose into the circulation
- Enzyme: glucose 6-phosphatase
Where does it occur?
Liver and kidneys only
Muscle lacks glucose-6-phosphatase
Muscle glycogen can only be used by muscle itself
Gluconeogenesis: Energy Expenditure
- Requires six phosphoanhydride bonds for the synthesis of one glucose molecule from two molecules of pyruvate or lactate Pyruvate carboxylase : 2 ATP PEP-carboxykinase: 2 GTP Phosphoglycerate kinase : 2 ATP - Oxidizes 2 NADH back to NAD+
- is the process of synthesizing glucose or
glycogen from noncarbohydrate precursors - The major substrates are the glucogenic amino acids, lactate, glycerol, and propionate.
Gluconeogenesis
Mitochondrial ___ catalyzes the carboxylation of pyruvate to oxaloacetate, an ATP-requiring reaction in which the vitamin biotin is the coenzyme
pyruvate carboxylase
A second enzyme, ___, catalyzes the decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate using GTP as the phosphate donor
phosphoenolpyruvate carboxykinase
– hormones that are responsive to a decrease in blood glucose, inhibit glycolysis and stimulate gluconeogenesis in the liver by increasing the concentration of cAMP.
Glucagon and epinephrine
In gluconeogenesis, pyruvate carboxylase, which catalyzes the synthesis of oxaloacetate from pyruvate, requires acetyl-CoA as an ___
allosteric activator
– Conversion of lactate to glucose
lactate generated during anaerobic metabolism
lactate brought to the liver where it is converted
to glucose via gluconeogenesis
glucose brought back to muscles and RBC
–Energy expense: 4 ATP molecules
Cori Cycle
Gluconeogenesis: Metabolic Cost
►Gluconeogenesis is energetically expensive
►The sum of the biosynthetic reactions from pyruvate to free blood glucose:
2 Pyruvate + 4ATP + 2GTP + 2NADH + H+ + H2O
-> Glucose + 4ADP + 2GDP + 6Pi + 2NAD+
►ATP requirement of gluconeogenesis is supplied by the oxidation of fatty acids
►A defect in fatty acid oxidation will manifest as hypoglycemia
Regulation of Gluconeogenesis
Regulated primarily by:
1. circulating levels of glucagon
Phosphorylates pyruvate kinase
Increases the transcription of the PEP carboxykinase
gene
2. availability of glucogenic substrates
3. allosteric activation by acetyl CoA- inhibits pyruvate dehydrogenase and diverts pyruvate towards gluconeogenesis
4. allosteric inhibition by AMP - inhibits fructose-1,6-bisphosphatase
- high amount of cytoplasmic NADH is formed by alcohol dehydrogenase and acetaldehyde dehydrogenase
- high amount of NADH favors the following reactions:
pyruvate»_space; lactate
OAA»_space; malate
DHAP»_space; glycerol-3-phosphate
Alcoholism and hypoglycemia
- High fetal glucose consumption
- Risk of maternal and fetal hypoglycemia especially
during fasting - Hyperinsulinemia: due to ↑estrogen leading to fasting hypoglycemia
- Insulin resistance: due to ↑HPL leading to post-
prandial hyperglycemia
Hypoglycemia during pregnancy
- Premature and LBW babies have little adipose tissue
- Enzymes of gluconeogenesis are not yet completely functional
Hypoglycemia in the neonate
- is the process of synthesizing glucose or glycogen from noncarbohydrate precursors
- Major substrates
Glucogenic amino acids
Lactate
Glycerol
Propionate (in ruminants)
Gluconeogenesis
- Liver and kidney -> major gluconeogenic tissues
– Small intestine may also be a source of glucose in the fasting state - The only source of glucose during prolonged fasting
Gluconeogenesis
- Major storage carbohydrate in animals
- Branched polymer of α-D-glucose
α(1->4) glycosidic bonds: for elongation - primary bond, about 8-10 glucose residues
α(1->6) glycosidic bonds: for branching
Where is it stored?
liver 100 g = 6% of liver
muscle 400 g =
Glycogen
If monosaccharides are connected by glycosidic
bonds, what do you call the bonds that connect amino acids?
Peptide
- Synthesis of new glycogen molecules from α-D- glucose
Where does it occur?
- Occurs in the liver and the muscle
- Occurs in the cytosol
Glycogenesis
Glycogenesis: What are the substrates and product?
Substrates: UDP-glucose
ATP and UTP
glycogenin: a core, primer protein
Product: Glycogen
Glycogenesis: Which step is rate-limiting?
Reaction: elongation of glycogen, i.e., addition of α(1->4) bonds
Enzyme: glycogen synthase
Glycogenesis
Glucose-6-P -> Glucose-1-P
Enzyme: phosphoglucomutase
This is a reversible process and is not rate-limiting
Synthesis of UDP-Glucose
Enzyme: UDP-glucose phosphorylase
Substrates: glucose-1-P and UTP
- The rate-limiting step of glycogenesis
- Enzyme: glycogen synthase
- Forms α(1->4) bonds between glucose residues
- Bonds formed at the non-reducing end (i.e., carbon 4)
Glycogenesis
- Enzyme: branching enzyme composed of amylo α(1->4) -> α(1->6) transglucosidase
- Forms new α(1->6) bonds by transferring 5 to 8
glucosyl residues
Formation of branches in glycogen
- Shortening of glycogen chains to produce molecules of α-D-glucose
Location:
Occurs in the liver and the muscle
Occurs in the cytosol
Glycogenolysis
Glycogenolysis
Substrate: Glycogen
- Leaves about 4 glucose residues before a branch point
called a limit dextrin
Products: Glucose-1-P and Free glucose
- Liver: can release free glucose to circulation
- Muscle: limited to glucose-6-P within muscle only
- Free glucose is a product of the debranching process
Glycogenolysis: Rate Limiting Step
Reaction: removal of glucose (breaks a(14) bonds)
Enzyme: glycogen phoshporylase
Enzymes: debranching enzyme composed of α(1->4) -> α(1->4) glucantransferase amylo-α(1->6) glucosidase Bonds cleaved: α(1->4) and α(1->6) Products: free glucose from the breakage of the α(1->6) bond
Removal of branches
Glycogenolysis
Conversion of glucose-1-P to glucose-6-P
Enzyme: phosphoglucomutase
Liver: glucose-6-P further converted to glucose
Muscle: glucose-6-P is the final product
Lysosomal degradation of glycogen
Enzyme: α(1->4) glucosidase
Also known as acid maltase, an enzyme that is different from glycogen phosphorylase
- Group of inherited disorders characterized by deposition of an abnormal type or quantity of glycogen in the tissues
- 12 types total, all of which are due to enzyme deficiencies
Abnormal glycogen metabolism
Accumulation of glycogen within cells
Glycogen Storage Diseases
- Type I
- deficiency in glucose 6- phosphatase
- causes glycogen in liver and renal cells hypoglycemia + lactic acidosis/ketosis
Von Gierke’s
- Type II
- deficiency in acid maltase
- glycogen in lysosomes cardiomegaly and heart failure
Pompe’s
- Type III
- debranching enzyme deficiency
- milder form of Type I
Cori’s
- Type IV
- branching enzyme deficiency
- severe form of Type I (early death from heart and liver failure)
Andersen’s
- Type V
- skeletal muscle glycogen phosphorylase deficiency
- glycogen in muscle
- muscle cramps + myoglobinuria but
- NO lactic acidosis
McArdle’s
- Type VI
- hepatic glycogen phosphorylase
- glycogen in liver cells hypoglycemia
Hers’
Blood Glucose Level
►After a carbohydrate meal = 6.5 – 7.2 mmol/L
►Post-absorptive state = 4.5 – 5.5 mmol/L
►Fasting = 3.3 – 3.9 mmol/L
Sources of Blood Glucose
- From carbohydrates in diet
Glucose
Galactose and fructose are readily converted to glucose in liver
2.From glucogenic compounds that undergo gluconeogenesis - From liver glycogen by glycogenolysis
Glucogenic Compounds that Undergo Gluconeogenesis
- Those involved in direct net conversion to glucose without significant recycling - Amino acids, propionate
- Those which are products of partial metabolism of glucose
Lactate – reforms glucose through Cori Cycle
Alanine – through Glucose – Alanine Cycle
Glycerol
- Regulate blood glucose after a meal through glucokinase activity
- Freely permeable to glucose which is then phosphorylated by glucokinase (in direct contrast to extrahepatic cells which are relatively impermeable to glucose but on entry is phosphorylated by hexokinase)
Liver
GLUCOKINASE vs HEXOKINASE
►Hexokinase
Lower Km (higher affinity) for glucose
Inhibited by glucose 6-phosphate
►Glucokinase
Higher Km (lower affinity) for glucose
Not inhibited by glucose 6-phosphate
- Glucose filtered by glomeruli but reabsorbed by renal tubule
► Renal threshold for glucose = 9.5 – 10 mmol/L
► Reabsorption rate = 350 mg/min - When glomerular filtrate contains more glucose than can be reabsorbed -> GLYCOSURIA -> may indicate Diabetes Mellitus
Kidneys
- Produced by -> cells of islet of Langerhans in pancreas
- Secreted as direct response to hyperglycemia
- Enhance glucose transport by recruitment of glucose transporter in muscles and adipose tissue
- Increases hepatic glycolysis
Insulin
- Produced by A cells of islet of Langerhans
- Stimulated by hypoglycemia
- Increases glycogenolysis and gluconeogenesis
Glucagon
- Elevates blood glucose
- Antagonize action of insulin
- Decreases glucose uptake in certain tissues, e.g.
muscles - Mobilizes free fatty acid from adipose tissues
Anterior Pituitary Hormones (GH, ACTH)
- Secreted by adrenal cortex
- Increases gluconeogenesis
- Decreases utilization of glucose in extrahepatic tissues
Glucocorticoid
Secreted by adrenal medulla
Increases glycogenolysis in liver and muscles
Epinephrine
Diabetogenic action -> FBS elevated in hyperthyroidism
Thyroid hormone
DM Type I vs Type II
►Type I
Insulin is absent or deficient because the pancreas lacks or has defective B-cells
►Type II
Deficiency of insulin receptors; insulin level is
normal or may be elevated
