Module 3 Flashcards
1
Q
– 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
A
Metabolism
2
Q
Metabolic pathways fall into three categories.
A
- Anabolic pathways
- Catabolic pathways
- Amphibolic pathways
3
Q
- 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
A
Anabolic pathways
4
Q
- are involved in the breakdown of larger molecules, commonly involving oxidative reactions
- they are exothermic, producing reducing equivalents, and, mainly via the respiratory chain
A
Catabolic pathways
5
Q
– occur at the “crossroads” of metabolism, acting as links between the anabolic and catabolic pathways, for example, the citric acid cycle
A
Amphibolic pathways
6
Q
energy requirement for human being is met from ____
A
carbohydrates (40%-60%)
lipids (mainly triacylglycerol, 30%-40%)
protein (10%-15%)
7
Q
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 ____
A
obesity
8
Q
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 _____
A
emaciation, wasting, and, eventually, death
9
Q
– ample supply of carbohydrate, and the metabolic fuel for most tissues is glucose
A
Fed State
10
Q
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)
A
fasting state
11
Q
As glycogen reserves become depleted (in fasting state), amino acids arising from protein turnover are used for __
A
gluconeogenesis
12
Q
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 ___
A
insulin and glucagon
13
Q
– there is either impaired synthesis and secretion of insulin or impaired sensitivity of tissues to insulin action
A
diabetes mellitus
14
Q
All the products of digestion are metabolized to a
common product,___, which is then oxidized by the
citric acid cycle
A
acetyl-CoA
15
Q
– 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
A
Glucose
16
Q
is metabolized to pyruvate by the pathway of glycolysis
A
Glucose
17
Q
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 ____
A
oxidative phosphorylation
18
Q
– can also occur anaerobically (in the absence of oxygen) when the end product is lactate.
A
Glycolysis
19
Q
an alternative to part of the pathway of glycolysis
A
pentose phosphate pathway
20
Q
Triose phosphate intermediates in glycolysis give rise to the ___
A
glycerol moiety of triacylglycerols
21
Q
Pyruvate and intermediates of the citric acid cycle provide the carbon skeletons for the synthesis of ____
A
nonessential or dispensable amino acids
22
Q
– is the process of synthesizing glucose from noncarbohydrate precursors such as, lactate, amino acids, and glycerol
A
Gluconeogenesis
23
Q
Fatty acids may be oxidized to acetyl-CoA (B-oxidation) or esterified with glycerol, forming ___ as the body’s main fuel reserve.
A
triacylglycerol
24
Q
Acetyl-CoA formed by β-oxidation of fatty acids may
undergo three fates
A
- 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.
25
-- 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
26
-- 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
27
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
28
-- the nature of the substrates entering and metabolites leaving tissues and organs can be measured
tissue and organ level
29
-- 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
30
```
Amino acids (resulting from the digestion of dietary protein) and glucose (resulting from the digestion of carbohydrates)
are absorbed via the ____
```
hepatic portal vein
31
-- 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
32
-- glycogen synthesis
Glycogenesis
33
-- fatty acid synthesis
Lipogenesis
34
- - 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
35
-- are mainly triacylglycerol, and are hydrolyzed to monoacylglycerols and fatty acids in the gut, then reesterified in the intestinal mucosa
Lipids
36
- - 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
37
- - hydrolyzes the triacylglycerol (chylomicrons)
| - - releasing fatty acids that are incorporated into tissue lipids or oxidized as fuel
lipoprotein lipase
38
- - is the main fuel reserve of the body
- - It is hydrolyzed (lipolysis) and glycerol and nonesterified
(free) fatty acids are released into the circulation
Adipose tissue triacylglycerol
39
In the liver, newly synthesized triacylglycerol and triacylglycerol from chylomicron remnants is secreted into the circulation in __
very low density lipoprotein (VLDL)
40
Partial oxidation of fatty acids in the liver leads to __
ketone body production (ketogenesis)
41
- - 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
42
a precursor for the synthesis of glucose in the cytosol
oxaloacetate
43
-- contain the enzyme system for triacylglycerol synthesis
membranes of the endoplasmic reticulum
44
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
45
- - 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
46
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
47
True or False
```
Fatty acids (and ketone bodies formed from them) cannot
be used for the synthesis of glucose
```
True
48
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.
49
```
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
50
-- two amino acids that yield only acetyl-CoA on oxidation, and hence cannot be used for gluconeogenesis
lysine and leucine
51
-- amino acids that give rise to both acetyl-CoA and intermediates that can be used for gluconeogenesis
phenylalanine, tyrosine, tryptophan, and isoleucine
52
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
53
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
54
In the fasting state, the glucose transporter of muscle
| and adipose tissue ___ is in intracellular vesicles.
GLUT-4
55
The increase in secretion of ___ by α cells of
| the pancreas inhibits glycogen synthetase, and activates glycogen phosphorylase in the liver
glucagon
56
- - 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
57
___ 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)
58
as fasting is prolonged, the plasma concentration of ___ increases markedly
ketone bodies (acetoacetate and 3-hydroxybutyrate)
59
acetyl-CoA formed by oxidation of fatty acids in muscle inhibits pyruvate dehydrogenase, leading to an ___
accumulation of pyruvate
60
substrate for gluconeogenesis in the liver
glycerol
61
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
62
is the study of the roles of sugars in health and disease.
Glycobiology
63
is the entire complement of sugars of an organism, whether free or present in more complex molecules
glycome
64
-- the comprehensive study of glycomes, including genetic, physiological, pathological, and other aspects
Glycomics
65
Classification of Carbohydrates
1. Monosaccharides
2. Disaccharides
3. Oligosaccharides
4. Polusaccharides
66
- - 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
67
- - 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
68
-- 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
69
-- 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)
70
-- sugars composed of two monosaccharide residues linked by a glycoside bond
Maltose - Glucose and glucose
Sucrose - glucose and fructose
Lactose - Glucose and galactose
Disaccharides
71
- - are condensation products of three to ten monosaccharides
- - Most are not digested by human enzymes.
Oligosaccharides
72
-- 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
73
- - 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
74
-- 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
75
- - 24 to 30 glucose residues
- - α1 → 4 linkages in the chains
- - α1 → 6 linkages at the branch points
Amylopectin (80%-87%)
76
-- 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
77
- - animal starch
- - storage polysaccharide
- - more highly branched structure than amylopectin
- - Muscle glycogen
- - contain up to 60,000 glucose residues
Glycogen
78
- - 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
79
- - 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
80
- - structural polysaccharide in the exoskeleton of crustaceans and insects
- - N-acetyl-d-glucosamine units joined by β1 → 4 glycosidic bonds
Chitin
81
- - occurs in fruits
| - - a polymer of galacturonic acid linked α-1→ 4
Pectin
82
- - 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
83
- - Aka Mucoproteins
- - Proteins containing branched or unbranched oligosaccharide chains
- - occur in cell membranes
- - Glycosylation
- - 5% of the weight of cell membranes
Glycoproteins
84
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
85
-- 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
86
Fat is stored in ___, where it also serves as a thermal insulator in the subcutaneous tissues and around certain organs.
adipose tissue
87
Nonpolar lipids act as ___, allowing rapid propagation of depolarization waves along myelinated nerves
electrical insulators
88
Classification of Lipids
1. Simple Lipids
2. Complex Lipids
3. Precursor or Derived Lipids
89
___ include fats and waxes which are esters of fatty acids with various alcohols
Simple lipids
90
Groups of Simple Lipids
1. Fats -- Esters of fatty acids with glycerol. Oils are fats in the liquid state.
2. 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.
91
Groups of Complex Lipids
1. Phospholipids
2. Glycolipids (glycosphingolipids)
3. Other complex lipids
92
-- 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
93
-- Lipids containing a fatty acid, sphingosine, and carbohydrate
Glycolipids (glycosphingolipids)
94
- - Lipids such as sulfolipids and amino lipids
| - - Lipoproteins may also be placed in this category.
Other complex lipids:
95
-- 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
96
-- acylglycerols (glycerides), cholesterol, and cholesteryl esters are termed ___ because they are uncharged
neutral lipids
97
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
98
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
99
Nomenclature (Powerpoint)
1. Palmitic -- C16:0 or 16:0
- - #C : # double bonds
2. Linoleic -- C18:2 (9,12)
- - 18 Ϫ9,12
- - ώ-carbon (methyl carbon)
- - Ώ-6 family (18-12)
3. Linolenic Acid -- C18:3 (9,12,15) or 18 Ϫ9,12,15
100
Are there essential lipids?
Linoleic and linolenic acid (ADEK)
101
Are there essential amino acids?
- - Adults: 9
| - - Infants: 10 (arginine)
102
Are there essential carbohydrates?
NO
103
- - Contain No Double Bonds
| - - based on acetic acid (CH3—COOH)
Saturated Fatty Acids
104
Unsaturated fatty acids may be further subdivided as follows:
1. Monounsaturated (monoethenoid, monoenoic) -- acids,
containing one double bond.
2. Polyunsaturated (polyethenoid, polyenoic) -- acids, containing two or more double bonds.
3. Eicosanoids -- These compounds, derived from eicosa
(20-carbon) polyenoic fatty acids, comprise
the prostanoids, leukotrienes (LTs), and lipoxins (LXs).
105
-- 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
106
-- have the cyclopentane ring interrupted with an oxygen atom (oxane ring)
thromboxanes
107
- - 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
108
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
109
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
110
-- 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
111
True or False
Most Naturally Occurring Unsaturated Fatty Acids Have cis Double Bonds
True
112
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
113
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
114
- - 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
115
- - Main storage forms of fatty acids
| - - carbons 1 and 3 of glycerol are not identical when viewed in three dimensions
Triacylglycerols (Triglycerides)
116
-- 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
117
__ 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
118
has two long chain hydrocarbon tails
Phospholipids
119
is important in nervous transmission, as acetylcholine, and
| as a store of labile methyl groups
Choline
120
-- 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
121
absence of Dipalmitoyl lecithin from the lungs of premature infants causes __
respiratory distress syndrome
122
- - Ethanolamine or serine, respectively, replaces choline
| - - plays a role in apoptosis (programmed cell death)
Phosphatidylethanolamine (cephalin) and phosphatidylserine
123
-- 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
124
The combination of sphingosine plus fatty acid is known as
| __, a structure also found in the glycosphingolipids
ceramide
125
- - Give rise to cardiolipin
- - Found only in mitochondria
- - Alterations in function or decreased levels associated in heart failure and hypothyroidism and aging
Phosphatidylglycerol
126
- - 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)
127
-- 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)
128
- - major glycosphingolipid of brain and other nervous tissue
- - Converted to sulfatide (present in high amounts in myelin)
Galactosylceramide
129
- - resembles galactosylceramide
- - head group is glucose rather than galactose
- - predominant simple glycosphingolipid of extraneural tissues
Glucosylceramide
130
-- complex glycosphingolipids derived from glucosylceramide
-- Function in cell-cell recognition and communication and as receptors for hormones and bacterial toxins (cholera)
GM1
Gangliosides
131
- - Precursor is cholesterol
- - Bile Acids
- - Adrenocortical hormones
- - Sex hormones
- - Vitamin D
- - Cardiac glycosides
Steroids
132
-- is a Precursor of Vitamin D
Ergosterol
133
- - 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
134
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
135
To control and reduce lipid peroxidation, both humans in
| their activities and nature invoke the use of ___
antioxidants
136
2 classes of antioxidant
1. preventive antioxidants -- reduce the rate of chain initiation
- - eg Catalase; EDTA; DTPA; Glutathione peroxidase
2. chain-breaking antioxidants -- interfere with chain propagation
- - eg Superoxide dismutase; vitamin E
137
- - 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
138
-- 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
139
Functions of Citric Acid Cycle
1. Provides majority of ATP for energy
2. Interconverts amino acids (transaminationdeamination)>>creates amino acids or destroys amino acids (producing glucose)
3. Has a crucial role in fatty acid synthesis
140
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
```
141
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
```
142
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
```
143
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
144
ATP Yield from TCA: Acetyl-CoA
ATPs from substrate level phosphorylation: 1
ATPs from NADH: 9
ATPs from FADH2: 2
TOTAL ATP YIELD: 12
145
ATP Yield from TCA: Pyruvate
ATPs from substrate level phosphorylation: 1
ATPs from NADH: 12
ATPs from FADH2: 2
TOTAL ATP YIELD: 15
146
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
147
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)
148
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
149
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
150
Regulatory Mechanisms- Suspected Mechanisms:
1. Pyruvate Dehydrogenase
2. Allosteric Inhibition of Citrate Synthase by ATP and long-chain fatty Acyl CoA
3. Allosteric Activation of mitochondrial NADdependent
IDH
4. Inhibition of Succinate dehydrogenase by oxaloacetate
5. Concentration of oxaloacetate
151
Inhibitors of the Citric Acid Cycle
1. Fluoroacetate - inhibit conversion of citrate to cis-aconitate
2. Arsenite - inhibit alpha ketoglutarate to succinyl coa
3. Malonate - inhibit conversion of succinate to fumarate
152
- Major pathway for glucose metabolism (but also for
galactose and fructose)
- Made up of 10 Steps
- Can work with or without oxygen
Glycolysis
153
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
154
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
155
Types of Glycolysis
1. Anerobic Glycolysis
In cells without a mitochondria (e.g. RBCs) or anoxic cells
(e.g. white muscle)
Final product: Lactate
2. Aerobic Glycolysis
In cells with a mitochondria and adequate supply of oxygen
Final Product: Pyruvate
156
2 Stages of Glycolysis
1. Energy Investment Phase - uses ATP
- Phosphorylated forms of intermediates are synthesized at
the expense of ATP
2. Energy Generation Phase - produce ATP
- 2 molecules of ATP are formed by substrate level
phosphorylation
157
Irreversible Steps in Glycolysis
1. Phosphorylation of glucose
3. Phosphorylation of fructose 6-phosphate – Rate-limiting
step of Glycolysis
10. Formation of pyruvate
158
- Present in most tissues
- Can phosphorylate glucose, fructose, galactose
- Inhibited allosterically by Glucose 6P
- Low Km
- High affinity for glucose
- Low Vmax
Hexokinase
159
- 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
160
Fructose 6P->Fructose 1,6BP
- Enzyme: phosphofructokinase-1 (PFK-1)
- Irreversible and rate-limiting step of glycolysis
- PFK-1 is different from PFK-2!
161
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
```
2. PFK-2
Converts Fructose 6P to Fructose 2,6BP
Inhibited by ↓insulin, ↑glucagon (starvation)
Activated by ↑insulin, ↓glucagon (well fed)
162
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
163
Steps involved in the Production of ATP
| Glycolysis
1. 1,3-bisphosphoglycerate->3-phosphoglycerate
Enzyme: phosphoglycerate kinase
2. PEP->pyruvate
Enzyme: pyruvate kinase
164
- The most common enzyme defect in glycolysis
- Manifests as chronic hemolytic anemia
* Aldolase A deficiency may also cause hemolytic anemia
Pyruvate Kinase Deficiency
165
Patients have low exercise capacity, particularly on high
| carbohydrate diets
Muscle Phosphofructokinase Deficiency
166
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
167
Glycolysis: NADH converted to ATP;
| transported using shuttles:
1. Malate Aspartate Shuttle
yields 3 ATPs each
liver, kidney and heart
2. Glycerol Phosphate Shuttle
yields 2 ATPs each
skeletal muscle and brain
168
Anaerobic Glycolysis:
Pyruvate is converted to lactate by the action of Lactate Dehydrogenase
169
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
170
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
171
Pyruvate to Acetyl Coa - Co-enzymes:
1. Thiamine pyrophosphate
2. FAD
3. NAD+
4. Coenzyme A (contains pantothenic acid)
5. Lipoic acid
172
- 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
173
- 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
174
Chronic alcoholics are prone to thiamine-deficiency and may develop potentially fatal pyruvic and lactic acidosis
Chronic alcoholism
175
Fates of Pyruvate
1. Lactate (Lactate dehydrogenase) - Anaerobic
2. Ethanol (Pyruvate decarboxylase) - Yeast and certain microorganisms
3. Acetyl Coa (Pyruvate dehydrogenase) - Aerobic
4. Oxaloacetate (Pyruvate carboxylase) - final step in gluconeogenesis
176
ATP Yield of Glycolysis
Anaerobic: 4
Aerobic: 4
177
- 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
178
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
179
Function of NADPH
1. Lipid Synthesis
2. Create antioxidant form of glutathione
3. Create Oxygen Free radicals to kill bacteria
180
Pentose Phosphate Pathway: Where does it occur?
In the cytoplasm
181
it is required for synthesis of DNA and RNA (which is made up of nucleotides)
Ribose 5-phosphate
182
Pentose Phosphate Pathway: What are the substrates?
Glucose-6-P
| No consumption or production of ATP
183
Pentose Phosphate Pathway: What are the products?
ribose-5-P, fructose-6-P, and glyceraldehyde-3-P
| NADPH
184
Pentose Phosphate Pathway: Which step is rate-limiting?
Reaction: glucose-6-P --> 6-phosphogluconate
Enzyme: glucose-6-P dehydrogenase
185
Pentose Phosphate Pathway: ACTIVE in the ff sites
```
Liver
Adipose tissue
Adrenals, thyroid and testes
RBC
LACTATING mammaries
```
186
Pentose Phosphate Pathway: LOW in the ff sites
Skeletal muscle
| NON-LACTATING mammaries
187
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
188
cofactor of transketolase for it to work
Thiamine
189
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
190
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!)
191
- transfers two carbon unit of a ketose onto the aldehyde carbon of an aldose sugar
- Co-factors: Mg2+ and Vitamin B1 (Thiamine)
Transketolase enzyme
192
- 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
193
- 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
194
altered hemoglobin that precipitates within RBCs; irregular precipitates of denatured Hgb
Heinz bodies
195
altered RBCs due to phagocytic removal of Heinz bodies in spleen
Bite Cells
196
- 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
197
- Another alternative pathway for glucose
- Zero ATP is used or produced
- Cellular site: cytoplasm
- Organ site: Liver
Uronic Acid Pathway
198
- 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
199
- 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
200
cofactor of Glutathione Peroxidase
Selenium
201
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
202
- 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
203
- 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
204
2 ALDOLASES
aldolase A and aldolase B
1. Aldolase A: for glycolysis
fructose-1,6-BP -> DHAP + glycerol-3-P
2. Aldolase B: for fructose metab
fructose-1-P -> DHAP + glyceraldehyde
205
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
206
- defect in fructokinase
| - benign and asymptomatic whose only symptom is the appearance of fructose in blood and urine
Essential Fructosuria or fructokinase deficiency
207
- 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
208
- 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
209
- Enzyme: aldose reductase
| - Found in lens, retina, Schwann cells, liver, kidney, placenta, RBC, ovaries, seminal vesicles
Glucose -> Sorbitol
210
- Enzyme: sorbitol dehydrogenase
| - Found in the seminal vesicles since fructose is the fuel of sperm
Sorbitol -> Fructose
211
- 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
212
- 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
213
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
214
- causes galactosemia and galactosuria
- cataracts in early childhood
- treatment: eliminate sources of galactose from the diet
Galactokinase Deficiency
215
- 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
216
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
217
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
218
-- 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
219
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
220
Production of glucose from the following intermediates
1. intermediates of glycolysis and the TCA
2. glycerol from triacylglycerols
3. lactate through the Cori Cycle
4. carbon skeletons (alpa-ketoacids) of glycogenic amino acids
Gluconeogenesis
221
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
222
Gluconeogenesis: What is the substrate and product?
Substrate: Pyruvate
Product: Glucose
223
Which step is rate-limiting?
Reaction: Fructose 1,6-biphosphate -> Fructose 6-Phosphate
Enzyme: Fructose 1,6-biphosphatase
224
- another substrate of gluconeogenesis
Glycerol
225
- enters main gluconeogenic pathway via citric acid cycle after conversion of succinyl Coa
- a major precursor of glucose in ruminants
Propionate
226
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.
227
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
228
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
229
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+
```
230
- is the process of synthesizing glucose or
glycogen from noncarbohydrate precursors
- The major substrates are the glucogenic amino acids, lactate, glycerol, and propionate.
Gluconeogenesis
231
Mitochondrial ___ catalyzes the carboxylation of pyruvate to oxaloacetate, an ATP-requiring reaction in which the vitamin biotin is the coenzyme
pyruvate carboxylase
232
A second enzyme, ___, catalyzes the decarboxylation and phosphorylation of oxaloacetate to phosphoenolpyruvate using GTP as the phosphate donor
phosphoenolpyruvate carboxykinase
233
-- 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
234
In gluconeogenesis, pyruvate carboxylase, which catalyzes the synthesis of oxaloacetate from pyruvate, requires acetyl-CoA as an ___
allosteric activator
235
-- 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
236
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
237
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
238
- high amount of cytoplasmic NADH is formed by alcohol dehydrogenase and acetaldehyde dehydrogenase
- high amount of NADH favors the following reactions:
pyruvate >> lactate
OAA >> malate
DHAP >> glycerol-3-phosphate
Alcoholism and hypoglycemia
239
- 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
240
- Premature and LBW babies have little adipose tissue
| - Enzymes of gluconeogenesis are not yet completely functional
Hypoglycemia in the neonate
241
- is the process of synthesizing glucose or glycogen from noncarbohydrate precursors
- Major substrates
Glucogenic amino acids
Lactate
Glycerol
Propionate (in ruminants)
Gluconeogenesis
242
- 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
243
- 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
244
If monosaccharides are connected by glycosidic
| bonds, what do you call the bonds that connect amino acids?
Peptide
245
- 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
246
Glycogenesis: What are the substrates and product?
Substrates: UDP-glucose
ATP and UTP
glycogenin: a core, primer protein
Product: Glycogen
247
Glycogenesis: Which step is rate-limiting?
Reaction: elongation of glycogen, i.e., addition of α(1->4) bonds
Enzyme: glycogen synthase
248
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
249
- 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
250
- 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
251
- Shortening of glycogen chains to produce molecules of α-D-glucose
Location:
Occurs in the liver and the muscle
Occurs in the cytosol
Glycogenolysis
252
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
253
Glycogenolysis: Rate Limiting Step
Reaction: removal of glucose (breaks a(14) bonds)
Enzyme: glycogen phoshporylase
254
```
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
255
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
256
- 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
257
- Type I
- deficiency in glucose 6- phosphatase
- causes glycogen in liver and renal cells hypoglycemia + lactic acidosis/ketosis
Von Gierke’s
258
- Type II
- deficiency in acid maltase
- glycogen in lysosomes cardiomegaly and heart failure
Pompe’s
259
- Type III
- debranching enzyme deficiency
- milder form of Type I
Cori’s
260
- Type IV
- branching enzyme deficiency
- severe form of Type I (early death from heart and liver failure)
Andersen’s
261
- Type V
- skeletal muscle glycogen phosphorylase deficiency
- glycogen in muscle
- muscle cramps + myoglobinuria but
- NO lactic acidosis
McArdle’s
262
- Type VI
- hepatic glycogen phosphorylase
- glycogen in liver cells hypoglycemia
Hers’
263
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
264
Sources of Blood Glucose
1. From carbohydrates in diet
Glucose
Galactose and fructose are readily converted to glucose in liver
2.From glucogenic compounds that undergo gluconeogenesis
3. From liver glycogen by glycogenolysis
265
Glucogenic Compounds that Undergo Gluconeogenesis
1. Those involved in direct net conversion to glucose without significant recycling - Amino acids, propionate
2. Those which are products of partial metabolism of glucose
Lactate – reforms glucose through Cori Cycle
Alanine – through Glucose – Alanine Cycle
Glycerol
266
- 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
267
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
268
- 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
269
- 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
270
- Produced by A cells of islet of Langerhans
- Stimulated by hypoglycemia
- Increases glycogenolysis and gluconeogenesis
Glucagon
271
- 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)
272
- Secreted by adrenal cortex
- Increases gluconeogenesis
- Decreases utilization of glucose in extrahepatic tissues
Glucocorticoid
273
Secreted by adrenal medulla
| Increases glycogenolysis in liver and muscles
Epinephrine
274
Diabetogenic action -> FBS elevated in hyperthyroidism
Thyroid hormone
275
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
