Biochemistry (mathews 3rd ed)

Hypoxanthine can be converted to xanthine by the enzyme xanthine oxidase in the reaction that follows: Hypoxanthine + O2 Xanthine + H2O2 In addition, hypoxanthine can be converted back

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What is Biochemistry?

Goals of Biochemistry

Describe structure, organization, function of cells in molecular terms.

Structural Chemistry Metabolism

Molecular Genetics

Wohler's synthesis of urea Buchners' fermentation of sugar from yeast extracts Sumner's crystallization of urease

Flemming's discovery of chromosomes Mendel's characterization of genes Miescher's isolation of nucleic acids Watson and Crick's structure of DNA

Biochemistry as a Discipline

Biochemistry as a Chemical Science

Amino acids Sugars Lipids Nucleotides Vitamins Hormones

Chemical Elements of Living Matter( Figure 1.4, Table 1.1)

Amino acid/Polypeptides (Figure 1.6)

Biochemistry as a Biological Science

Distinguishing Characteristics of Living Matter

Constant renewal of a highly ordered structure accompanied by an increase in complexity of that structure

Overcoming entropy requires energy

Life is self-replicating

Unit of Biological Organization: The Cell ( Figure 1.8, Figure 1.9)

Prokaryotes (Table 1.2)

Eubacteria Archaebacteria Eukaryotes (Compartmentalization of organelles) (Figure 1.11, Figure 1.13)

Windows on Cellular Functions: The Viruses

New Tools in the Biological Revolution (Figure 1.15)

The Uses of Biochemistry

What is Biochemistry?

Goals of Biochemistry

Describe structure, organization, function of cells in molecular terms

Structural ChemistryMetabolism

Molecular Genetics

Roots of Biochemistry (Figure 1.3)

Wohler's synthesis of ureaBuchners' fermentation of sugar from yeast extractsSumner's crystallization of urease

Flemming's discovery of chromosomesMendel's characterization of genesMiescher's isolation of nucleic acidsWatson and Crick's structure of DNA

Biochemistry as a Discipline

Biochemistry as a Chemical Science

Amino acids Sugars

Lipids Nucleotides Vitamins Hormones Chemical Elements of Living Matter( Figure 1.4, Table 1.1)

Biological Molecules

Monomers/Polymers (Figure 1.7)

Sugar/Polysaccharide Nucleotide/Nucleic Acids Amino acid/Polypeptides (Figure 1.6)Biochemistry as a Biological Science

Distinguishing Characteristics of Living Matter

Constant renewal of a highly ordered structure accompanied by an increase

in complexity of that structureOvercoming entropy requires energyLife is self-replicating

Unit of Biological Organization: The Cell ( Figure 1.8, Figure 1.9)

Prokaryotes (Table 1.2)

EubacteriaArchaebacteria

Eukaryotes (Compartmentalization of organelles) (Figure 1.11, Figure 1.13)

Windows on Cellular Functions: The Viruses

New Tools in the Biological Revolution(Figure 1.15)

The Uses of Biochemistry

Agriculture

Medicine

Nutrition

Clinical Chemistry Pharmacology

Toxicology

Figure 1.1: Medical applications of biochemistry.

6-Mercaptopurine is an analog of hypoxanthine, an

intermediate in purine nucleotide biosynthesis When

mercaptopurine is made into a nucleotide by a cell, it stops DNA replication from occurring because it is incorporated into DNA by DNA polymerase instead of the proper

nucleotide

6-Mercaptopurine is an anticancer medication It inhibits the

uncontrolled DNA replication associated with proliferation of white blood cells in leukemia

See also: DNA, Purines, De Novo Biosynthesis of Purine

Nucleotides, DNA Replication Overview

Hypoxanthine is a base found in an intermediate of purine

nucleotide biosynthesis Figure 22.4 summarizes the pathway

leading from phosphoribosyl-1-pyrophosphate (PRPP) to the first

fully formed purine nucleotide, inosine 5'-monophosphate (IMP),

also called inosinic acid IMP contains as its base, hypoxanthine.

Hypoxanthine is also a product of catabolism of purine nucleotides ( Figure 22.7) Hypoxanthine can be converted to xanthine by the enzyme xanthine oxidase in the reaction that follows:

Hypoxanthine + O2 <=> Xanthine + H2O2

In addition, hypoxanthine can be converted back to IMP in purine nucleotide salvage biosynthesis (by

the enzyme HGPRT), as shown in Figure 22.9

Complete deficiency of HGPRT results in gout-related arthritis, dramatic malfunction of the nervous system, behavioral disorders, learning disability, and hostile or aggressive behavior, often self directed

In the most extreme cases, patients nibble at their fingertips or, if restrained, their lips, causing severe self-mutilation

Allopurinol, which is similar to hypoxanthine (see here), is used to treat gout because it inhibits

xanthine oxidase , leading to accumulation of hypoxanthine and xanthine, both of which are more soluble and more readily excreted than uric acid, the chemical that causes gout

See also: De Novo Biosynthesis of Purine Nucleotides, Purine Degradation, Excessive Uric Acid in Purine Degradation, Salvage Routes to Deoxyribonucleotide Synthesis , Nucleotide Analogs in Selection

INTERNET LINKS:

1 Purine Metabolism

2 Purine and Pyrimidine Metabolism

Figure 22.4: De novo biosynthesis of the purine ring, from PRPP to inosinic acid.

Phosphoribosyl Pyrophosphate (PRPP)

PRPP is an intermediate in nucleotide

metabolism It is found in several de

novo and salvage pathways PRPP is

formed by action of the enzyme, PRPP

(de novo purine synthesis)

See also: De Novo Biosynthesis of Purine Nucleotides, De Novo Pyrimidine Nucleotide Metabolism,

Nucleotide Salvage Synthesis

Phosphribosyl Pyrophosphate Synthetase (PRPP Synthetase)

PRPP synthetase is an enzyme that catalyzes there reaction below (see here also):

ATP + Ribose-5-Phosphate <=> PRPP + AMP

PRPP is an important intermediate in the de novo synthesis of purines pathway (Figure 22.4) Defects

in PRPP synthetase may render it insensitive to feedback inhibition by purine nucleotides Thus, purine nucleotides are overproduced, leading to excessive uric acid synthesis and gout (Figure 22.9)

See also: The Importance of PRPP, De Novo Biosynthesis of Purine Nucleotides, Excessive Uric Acid in Purine Degradation

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Adenosine Triphosphate (ATP)

ATP serves as the

general "free energy

currency" for virtually

all cellular processes

contraction, and the

specific transport of substances across membranes The processes of photosynthesis and metabolism of

nutrients are used mainly to produce ATP It is probably no exaggeration to call ATP the single most

important substance in biochemistry The average adult human generates enough metabolic energy to

synthesize his or her own weight in ATP every day.

ATP is produced in the cell from ADP as a result of three types of phosphorylations - substrate-level

phosphorylations, oxidative phosphorylation, and, in plants, photosynthetic phosphorylation

ATP is a source of phosphate energy for synthesis of the other nucleoside triphosphates via the reaction

that follows:

ATP + NDP <=> ADP + NTP (catalyzed by Nucleoside Diphosphokinase)

ATP is also an allosteric effector of many enzymes.

See also: Nucleotides, ATP as Free Energy Currency (from Chapter 12), ADP, AMP, Figure 3.7

Adenosine Diphosphate (ADP)

ADP is a nucleotide

produced as a result of

hydrolysis of ATP in the

most common

energy-yielding reaction of cells

possible to list here all of

the enzymes interacting

with ADP Metabolism of

ADP is shown below:

1 ADP <=> ATP + AMP (catalyzed by adenylate kinase)

2 GMP + ATP <=> GDP + ADP (catalyzed by guanylate kinase)

3 NDP + ATP <=> NTP + ADP (catalyzed by nucleoside diphosphokinase)

4 ADP + NADPH <=> dADP + NADP+ (catalyzed by ribonucleotide reductase)

ADP is transferred into the mitochondrial matrix by adenine nucleotide translocase and may be a

limiting reagent in oxidative phosphorylation

See also: Phosphorylations , AMP, ATP

Adenosine Monophosphate (AMP)

AMP is a common intermediate in

metabolism involving ATP

AMP is produced as a result of

energy-yielding metabolism of ATP in three

C By transfer of a pyrophosophate from

ATP to another metabolite (reaction 6 below)

AMP is also an intermediate in de novo synthesis of ATP (reaction 3 below) and salvage synthesis of

ATP (reactions 4, 5, and 8 below) AMP is an allosteric activator of glycogen phosphorylase b , and phosphofructokinase, as well as an allosteric inhibitor of fructose-1,6-bisphosphatase and

adenylosuccinate synthetase AMP is also an allosteric inhibitor of glutamine synthetase, an enzyme with a central role in nitrogen metabolism in the cell

Selected reactions involving AMP

1 Fatty acid + ATP + CoASH <=> Fatty acyl-CoA + AMP + PPi (catalyzed by Fatty

acyl-CoA Ligase)

2 2 ADP <=> ATP + AMP (catalyzed by Adenylate Kinase)

3 Adenylosuccinate <=> Fumarate + AMP (catalyzed by Adenylosuccinate Lyase)

4 PRPP + Adenine <=> AMP + PPi (catalyzed by Phosphoribosyltransferase)

5 ATP + Ribose-5-Phosphate <=> PRPP + AMP (catalyzed by PRPP Synthetase)

6 AMP + H2O <=> NH4+ + IMP (catalyzed by AMP Deaminase)

See also: ATP , ADP, cAMP, AMP-Dependent Protein Kinase

Two features distinguish glycogen phosphorylase b from the a form:

1 The a form is derived from the b form by phosphorylation of the b form by the enzyme

phosphorylase b kinase (Figure 13.18)

2 The b form requires AMP for allosteric activation and is thus active only when cells are

at a low energy state

See also: Mechanism of Activating Glycogen Breakdown, Kinase Cascade, Glycogen Breakdown Regulation, Phosphorolysis, Glycogen, Glucose-1-Phosphate, cAMP

Glycogen Phosphorylase

Glycogen phosphorylase catalyzes phosphorolysis of glycogen to glucose-1-phosphate (Figure

13.18)

Two forms of the enzyme exist The relatively "inactive" form 'b' has no phosphate, but can be converted

to the more active form 'a' by action of the enzyme glycogen phosphorylase b kinase

Two features distinguish glycogen phosphorylase a from the b form:

1 The a form is derived from the b form by phosphorylation of the b form by the enzyme

phosphorylase b kinase

2 The b form requires AMP for allosteric activation and is thus active only when cells are

at a low energy state

See also: Glycogen Phosphorylase a, Glycogen Phosphorylase b, Glycogen , Kinase Cascade,

Glycogen Phosphorylase b Kinase, Figure 16.11

Phosphorolysis involves the cleavage of a bond by addition across that bond of the elements of

phosphoric acid An enzyme catalyzing a phosphorolysis is called a phosphorylase, to be distinguished

from a phosphatase (or, more precisely, a phosphohydrolase), which catalyzes the hydrolytic cleavage (hydrolysis) of a phosphate ester bond

Energetically speaking, the phosphorolytic mechanism has an advantage in mobilization of glycogen,

which yields most of its monosaccharide units in the form of sugar phosphates (glucose-1-phosphate) These units can be converted to glycolytic intermediates directly, without the investment of additional ATP By contrast, starch digestion yields glucose plus some maltose ATP and the hexokinase reaction are necessary to initiate glycolytic breakdown of these sugars

See also: Figure 13.15, Glycogen, Glucose-1-Phosphate, Starch, Glucose, Maltose, Hexokinase

Figure 13.15: Cleavage of a glycosidic bond by hydrolysis or phosphorolysis.

Glycogen is a branched polymer of glucose, consisting of main branches of glucose units joined in

(1->4) linkages Every 7-20 residues, (1->6) branches of glucose units are also present Glycogen is a

primary energy storage material in muscle Individual glucose units are cleaved from glycogen in a phosphorolytic mechanism catalyzed by glycogen phosphorylase

The storage polysaccharides, such as glycogen, are admirably designed to serve their function Glucose

and even maltose are small, rapidly diffusing molecules, which are difficult to store Were such small molecules present in large quantities in a cell, they would give rise to a very large cell osmotic pressure, which would be deleterious in most cases Therefore, most cells build the glucose into long polymers, so that large quantities can be stored in a semi-insoluble state Whenever glucose is needed, it can be

obtained by selective degradation of the polymers by specific enzymes

See also: Phosphorolysis, Glycogen phosphorylase , Figure 13.18, Kinase Cascade , Figure 13.16 , Figure 13.17, Polysaccharides, Glycogen Breakdown, Hydrolysis vs Phosphorolysis, Glycogen Breakdown Regulation

Glucose is a six carbon sugar which can provide a rapid source of

ATP energy via glycolysis Glucose is stored in polymer form by

plants (starch) and animals (glycogen) Plants also have cellulose,

which is not used to store glucose, but rather provides structural

integrity to the cells

Glucose has an anomeric carbon, which can exist in the and configurations Glucose can exist in

both the D and L forms (though the D-form predominates biologically) It can exist as a straight chain or

in ring structures composed of 5 (furanose) or 6 (pyranose) member rings

Metabolic pathways involving glucose

Other Saccharide Synthesis

See also: Diastereomers (from Chapter 9), Saccharides (from Chapter 9)

Glycolysis is a central metabolic pathway involving metabolism of the sugar glucose Figure 13.3

shows an overview of the process, being divided into a phase in which ATP energy is invested (see

here) and a phase in which ATP energy is generated (see here ) The starting point for glycolysis is the

molecule glucose and the process ends with formation of two pyruvate molecules Additional products

of glycolysis include two ATPs and two NADHs

See also: Glycolysis Reaction Summaries, Molecular Intermediates, Glycolysis/Gluconeogenesis Regulation, Gluconeogenesis, Aerobic vs Anaerobic Glycolysis, Pyruvate

INTERNET LINKS:

1 Glycolysis/Gluconeogenesis

Figure 13.3: An overview of glycolysis.

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NADH is a carrier of

electrons produced in

biological oxidations

The molecule exists in

two forms that vary in

whether or not they are

carrying electrons

NADH is the reduced

form of the molecule

(carries electrons) and

NAD+ is the oxidized

form of the molecule

(lacks electrons) NADH is produced from NAD+ in reactions such as conversion of acetaldehyde to

ethanol by alcohol dehydrogenase (Figure ) NADH is converted back to NAD+ by donating electrons (such as in the conversion of pyruvate to lactate) or by depositing electrons into the electron transport

system

NADH carries electrons to the electron transport system inside the mitochondrion via a shuttle system

(Figure 15.11) Electrons that enter via the shuttle in Figure 15.11a bypass complex I of the electron transport system, whereas electrons that enter via the shuttle in Figure 15.11b enter at complex I

In contrast to the reduced related compound, NADPH, which donates electrons primarily for

biosynthetic reactions, NADH primarily donates electrons to the electron transport system for energy

generation

See also: Lactic Acid Fermentation, Alcoholic Fermenation

NADH is a carrier of

electrons produced in

biological oxidations

The molecule exists in

two forms that vary in

whether or not they are

carrying electrons

NADH is the reduced

form of the molecule

(carries electrons) and

NAD+ is the oxidized

form of the molecule

(lacks electrons) NADH is produced from NAD + in reactions such as conversion of acetaldehyde to

ethanol by alcohol dehydrogenase (Figure ) NADH is converted back to NAD + by donating electrons (such as in the conversion of pyruvate to lactate) or by depositing electrons into the electron transport

system

NADH carries electrons to the electron transport system inside the mitochondrion via a shuttle system (Figure 15.11) Electrons that enter via the shuttle in Figure 15.11a bypass complex I of the electron transport system, whereas electrons that enter via the shuttle in Figure 15.11b enter at complex I

In contrast to the reduced related compound, NADPH, which donates electrons primarily for

biosynthetic reactions, NADH primarily donates electrons to the electron transport system for energy generation

See also: Lactic Acid Fermentation, Alcoholic Fermenation

INTERNET LINKS:

1 3D Structure

2 Nicotinate and Nicotinamide Metabolism

Acetaldehyde is a two carbon compound participating in the

reactions below:

1 Pyruvate <=> Acetaldehyde + CO2 (catalyzed in yeast by Pyruvate Decarboxylase)

2 Ethanol + NAD+ <=> Acetaldehyde + NADH (catalyzed by Alcohol Dehydrogenase)

3 Threonine <=> Acetaldehyde + Glycine (catalyzed by Threonine Aldolase)

See also: Alcoholic Fermentation

Pyruvic Acid (Pyruvate)

Pyruvate is the final product of glycolysis and a starting point for

gluconeogenesis Amino acids broken down through pyruvate include

alanine, cysteine, glycine, serine, threonine, and tryptophan

In anaerobic glycolysis , pyruvate is converted to lactate or ethanol

Enzymes that act on pyruvate include:

See also: Gluconeogenesis Enzymatic Reactions, Gluconeogenesis Molecular Intermediates,

Regulation of Gluconeogenesis and Glycogen, Glycolysis,

Figure 16.6: Major control mechanisms affecting glycolysis and gluconeogenesis.

Enzymes of Gluconeogenesis

Eleven reactions are catalyzed in glucoenogenesis The enzymes involved and the reactions they catalyze are listed below Glycolysis uses many of the same enzymes as gluconeogenesis, but with reversal of reaction direction Enzymes differing between glycolysis and gluconeogenesis are marked

* PEPCK (Glycolysis uses Pyruvate Kinase )

Pyruvate Carboxylase (Glycolysis uses Pyruvate Kinase )

See also: Glycolysis/Gluconeogenesis Regulation, Enzymes/Energies of Glycolysis,

Glucoenogenesis, Glycolysis

Glucose-6-phosphatase is an important enzyme for making glucose from G6P in tissues, such as liver

and kidney, that supply glucose to other tissues via the bloodstream The enzyme is not made

appreciably in muscles, which obtain glucose for use in glycolysis either from the bloodstream or as G6P from glucose-1-phosphate produced during glycogen catabolism The enzyme has been implicated

in von Gierke's disease, a glycogen storage disorder (see here)

See also: Glycolysis/Gluconeogenesis Regulation Links, Enzymes of Gluconeogenesis; Enzymes/ Energies of Glycolysis, Hexokinase, , Glycolysis, Glucose-1-Phosphate, Muscle Metabolism