Running head: ENZYMOLOGY & METABOLISM 1

Enzymology & Metabolism

Delia Garcia

GRT-1 Biochemistry

February 20, 2015

Julie Thompson
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Enzymology & Metabolism

Anthelme Brillat-Savarin, originally wrote (1826): Dis-moi ce que tu manges, je te

dirai ce que tu es; which translates to, tell me what you eat, and I will tell you what you are

(Swanson, 2014).When it comes to diet and nutrition, the time-honored aphorism, You are what

you eat remains true to this day. The statement is the simplest, yet most effective, illustration of

human metabolism and the biological molecules involved in the process. Metabolism is a series

of chemical reactions occurring within the cells of any living plant, person, substance, animal,

bacteria, or organism; and these reactions are necessary for sustaining life, thus when the

reactions end; life will also come to a halt.

The mechanisms of metabolism strategically involve the four essential molecules, nucleic

acids, proteins, carbohydrates, and fats (lipids). Most living organisms attain the necessary

macromolecules through consumption the subsequent digestion processes which break down the

nutrients in the food. Once we ingest food our body begins the process of digestion in order to

break down the food into the necessary subunits. The molecules are broken down into the lowest

monomer; for instance, protein becomes amino acid, carbohydrates become glucose, and fats

become fatty acids. As such, the process in which our bodies break down molecules for life in

metabolism is designated catabolism. Conversely, when we metabolize molecules in order to

build up tissues, such as muscle, or to support growth, this process is considered anabolism.

Anabolism requires energy to build up tissues within the body, and energy comes from

the ingesting and catabolizing of food, mainly glucose. The cycles involved in this process are

known as cellular respiration. Moreover, these ongoing processes are controlled by hormones,

which maintain the delicate balance required between the two metabolic states.

Hereditary Fructose Intolerance

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Glucose is the primary source of fuel or energy for the human body; in fact, the brain

requires the metabolism of glucose because it is able to pass the blood brain barrier. Patients with

Multiple Sclerosis, Alzheimers Disease, and Dementia suffer in part because of low brain

metabolism and thereby have a low glucose uptake. Simple carbohydrates, monosaccharides,

disaccharides, oligosaccharides, starches, non-starches, and complex carbohydrates all eventually

catabolize down to into glucose, which is then used to produce energy via ATP.

If the human body lacks the proper amount of glucose within its cells a hypo-metabolic

state will arise. A diet high in unsaturated fat can impede the efficient oxidation of glucose within

the cells as well as inhibit mitochondrial respirtation. This suppresses the immune system,

increases lipid peroxidation, decreases the production of C02 and increases the production of

toxic lactic acid within the tissues. Yet, instances of metabolic deficiency can occur that inhibit

metabolism, and therefore focus on action occurring at the cellular level must occur to

successfully mitigate the cause.

Fructose is important in human metabolism, in fact, Fructose is responsible for

catalyzing the oxidation of glucose to carbon dioxide to regulate metabolism and create

energy(East West Healing, 2012). Fructose can assist in the storage of glycogen within the liver

and improves the livers ability to phosphorylate glucose. According to East West Healing,

Fructose is important in sexual reproduction in seminal fluid and the placenta transforms

glucose from the mothers blood stream into fructose creating a high concentration of fructose

within the amniotic fluid to increase cellular metabolism and allow for growth (East West

Healing, 2012).

Hereditary Fructose Intolerance (HFI) occurs when an individual is lacking the enzyme

necessary to catabolize fructose, Aldolase B. Fructose is a sugar found naturally in the human
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body, in fruits, artificial sweeteners, and in sucrose or common table sugar. This genetic disorder

is passed down to offspring via a specific DNA mutation; in the event both parents carry the

Aldolase B mutation, each of their offspring will face a 25% chance of developing this disorder

as well.

Without this enzyme present in the body, the chemical reactions required to transform

carbohydrates into energy cannot occur properly, thus resulting in hypoglycemic episodes.

Fructose is typically transformed into Fructose-1 phosphate (F1P), which is the Aldolase B

substrate; then splits into glyceraldehyde and dihydroxyacetone phosphate. These products are

then ultimately synthesized into ATP via the glycolysis pathway in cellular respiration; or it

becomes stored in the tissues as glycogen.

Normally, F1P serves as a signaling agent for glucokinase which coaxes the substance out

of the liver to mediate high levels of glucose in the blood, however when this happens and the

blood glucose is already low due to HFI, serious disturbances will occur. Nevertheless, as the

body is unable to process fructose properly without the presence of Aldolase B, the ingested

fructose is only phosphorylated and continues generating the substrate F1P which is essentially

starved of the enzyme required to react with it. Therefore, as a result F1P begins to build up to

dangerous levels within the liver. While F1P increases, the phosphate pools within the liver begin

to rapidly deplete; which subsequently affect the process of cellular respiration occurring during

the electron transport chain phase.

As the assembly mechanism of ATP decelerates, the liver starts to experience significant

energy level depletion, impairment, and eventual failure. Typical presentation of this disorder

begins in infancy, once the child begins to consume either formula or baby food, symptoms

mimic those witnessed in galactosemia and hypoglycemia and tend to include shakiness,
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headache, irritability, fatigue, weakness, vomiting, seizure, and depending on severity possibly

gout and jaundice. Treating immediate complications and the removal of fructose from the diet

can generally improve symptoms and quality of life.

The Enzymatic Cycle

Enzymes help to maintain the delicate internal balance of cellular respiration and

metabolism. Enzymes can either release or absorb energy; as such neither type of reaction occurs

spontaneously. The fundamental roles of enzyme function include the escalation of reaction time

to yield necessary biological products and the capability to control the state of reactivity from

either high to low. Enzymes are specific types of proteins; examples of non-enzymatic proteins

include the antibodies, receptor, transport, and motor proteins. Conversely, enzymatic proteins

work to catalyze various chemical reactions, DNA polymerase, catalase, and amylase (saliva) are
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examples of enzymatic proteins. In addition, enzymes are not consumed by any single reaction,

unless denatured, but rather they increase the speed of a reaction or simply work to inhibit it.

Enzyme structure determines the particular function, and the active site is unique to and

will fit only the correlating substrate that it is supposed to bond and react with. Denaturation of

an enzyme will change its shape and render it ineffectual. Substrates are simply reactants, and

post reaction becomes a product, which is no longer usable as a substrate. The graph below

depicts the Lock and Key model, which is also christened as the Induced Fit Method; and is a

very simple representation of how the substrate enters the enzymes active site, and then forms

an initial bond and subsequent reaction thorough changing the substrate to promote an induction

of a taught union.

Enzymes require a proper environment in order to function. In humans, the pH must be

seven, the temperature must be around 98.6, and substrate concentrations need to be effectual,

not too high or too low. Reactions that cannot properly occur typically result in the progression

of disease. Enzymes speed up reactions and can also lower activation energy. Therefore, there are

times when the enzyme must be inhibited, to block reactions. Activation is the addition of

another element to increase activation energy. Co-factors and co-enzymes are small inorganic

compounds that serve as these activating influences.

Lowering the activation energy will inhibit the overproduction of reaction products. The

inhibitor will bond to the active site to prevent the substrate from bonding or by changing the

enzyme shape. Additionally, chemical reactions can occur without the enzyme present, yet the

results yielded will be remarkably less than in the presence of the enzyme. For Instance, a

reaction to produce a specific product will generally create 1,000 molecules without the
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enzymes presence. With the enzyme however, the speed of the reaction increases dramatically to

produce over 100,000 products in the same amount of time.

Enzyme Activation Diagram

In the image below, the substrate and the enzyme have not exactly formed a perfect

bond. However, in the next phase of the cycle the enzyme changes the shape of the substrate

which allows for that perfect fit. The reaction begins to break down the substrate by weakening

the bonds to the product; in preparation for ejecting it from its active site. Enzymes will remain

connected until the reaction is complete; and finally, the enzyme releases the product, and the

free enzyme can be used to perform further reactions.

The Lock & Key Model

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The Significance of the Presence of Oxygen, Lactic Acid, & the Cori Cycle

The Cori Cycle is an example of substrate cycling, and the process consists of converting

glucose into lactic acid and then back into glucose again. The Cori Cycle comprises two different

processes (glycolysis and gluconeogenesis) occurring simultaneously within the body, but not

within the same cell. These two processes occurring within the same cell are ultimately fruitless

as building up ATP and breaking it down concurrently will not yield any subsequent energy,

especially since more ATP is actually consumed within the cell, in turn creating a net loss of four

ATP per cycle. If the cycle were to remain within the confines of a single cell, the glucose
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would be used up and resynthesized at the expense of ATP and GTP hydrolysis which is entitled

the futile cycle (Nelson, 1985).

The Cori Cycle compensates for the lack of oxygen through the fermentation process

during this process lactate is taken from muscle tissues, by the blood, to the liver to be reoxidized

into pyruvate, and through gluconeogenesis back into glucose. In the absence of oxygen,

glycolysis essentially will detour pyruvate molecules and channel them into fermentation for

anaerobic metabolism. Fermentation has the capability to produce various products in different

organisms. For example, beer is the product of the fermentation of yeast.

In opposition, fermentation yields the product of lactic acid which builds up within

muscles in the absence of oxygen, and essentially is of no benefit to our system. In effect, lactate

is the product of anaerobic metabolism when the body is attempting to catabolize sugar, without

oxygen. When muscle tissue has used up all the available oxygen through either exercise which

has a symptomatic presentation of muscle pain or burning; or perhaps the body is unable to

maintain adequate profusion through disease, such as Sepsis or mitochondrial disease, and will

cause the body to go into compensatory mechanisms.

Compensatory mechanisms include increased heart rate and respiration and this is the

body attempting to draw in the oxygen in order to maintain adequate system profusion. The

amount of lactate present within the body provides a direct link the amount of oxygen profusion

at the cellular level. Therefore, because oxygen is such a vital molecule in all the mechanisms of

cellular respiration; glycolysis is unique for the reason that it can occur with or without the

presence of oxygen. The citric acid cycle however is an aerobic process, and requires oxygen to

initiate and ultimately bring the cycle to fruition.

The Cori Cycle

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Mitochondrial Processes & Disorders

Most studies designate defects of mutation occurring in nuclear genes are intricately

involved in mitochondrial oxidative metabolism (Taylor & Turnbull, 2007). As such, defects in

the mitochondria, whose primary function is to convert and store energy; the end result can

conceivably flaw reactions occurring during cellular respiration. Moreover, mtDNA mutations

are of maternal inheritance and appear with recognition of classic syndromes; for example,

mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, or chronic

progressive external ophthalmoplegia (Taylor & Turnbull, 2007). Any disorder of the

mitochondria is bound to wreak havoc upon all the processes which occur within this area, such

as energy production; in addition to the various CNS disturbances in the body.

If a defect occurs instead within a particular enzyme, rather than the mitochondria the

effects will likely inhibit metabolism. An enzymatic defect befalling an enzyme such as fumerate

hydratase, for example; occurs on a biochemical level; as such the aftermath will be exhibited in

the disruption of the conversion to malate. The interruption of malate production ultimately has
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an effect on gluconeogenesis and thus causes a reduction of energy in the form of NADH.

Maltase is normally oxidized into maltase dehydrogenase which supports the cells usage of

oxygen, without oxygen, the citric acid cycle is ultimately unable to transport acetyl CoA and

produce ATP.

Coenzyme Q10 (CoQ10) is an important factor in mitochondrial respiration, specifically

in the Electron Transport Chain; and it is found in almost all the cells of the body. CoQ10 assists

the cell in the production of energy by burning oxygen, as well as plays an important role in the

beta oxidation of fatty acids. CoQ10 is important to 90% of the production of ATP especially in

mitochondrial bioenergy transfer as it is responsible for electron transmission from protein

complex I to protein complex III. CoQ10 also assists in transporting two key proteins from

protein complex I to protein complex III. This co-enzyme is integral to many body functions and

processes and can be depleted with age as well as by medications used to treat high cholesterol.
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Cellular Respiration
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The Mitochondria

Processes of Cellular Respiration

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Enzymes catalyze reactions in every stage of cellular respiration which is the motivation

behind their significance. Cellular respiration is the process of turning the food we eat, into

energy in order to function, move, think, and power all the unseen processes which promote life.

The various phases of cellular respiration occur in a number of different parts within the cell,

such as the cytoplasm and the mitochondria. Nevertheless, all the biological reactions and

processes cannot be put into action without the energy provided by one vital molecule, ATP.

Adenosine Triphosphate: The Biological Currency of Energy

ATP is a form of stored energy, typically derived through the uptake of glucose, occurring

over three separate cycles; glycolysis, the citric acid cycle, and the electron transport chain. ATP

is comprised of the nitrogenous base, Adenine, and ribose sugar (adenosine), in addition to three

phosphate groups. ATP generates energy by ejecting the third phosphate group off the molecule.

Once the reaction occurs, and the energy is spent, an OH group comes in and attaches to the end

of the remaining two phosphate groups through hydrolysis. As such, the ATP molecule then

becomes ADP, or adenosine diphosphate; which is useful later in cellular respiration.

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Glycolysis

The process of glycolysis arises by means of oxygen and glucose catabolism. Whats

more, it is believed that one molecule of glucose can produce up to 38 molecules of ATP in a

high functioning cell. Glycolysis breaks down the hexose (six carbon rings) structure of glucose

into two, three carbon molecules of pyruvate. Through the work of various enzymes and an

initial capital outlay of two molecules of ATP, the process of glycolysis ultimately produces a net

total of four ATP molecules and two molecules of NADH. NADH is a high energy B vitamin

derivative in conjunction with positively charged electrons and hydrogen. NADH is useful later

in cellular respiration as the cycles progress.

The Citric Acid Cycle

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(a.k.a. The Krebs cycle/Tricarboxylic Acid Cycle)

The CAC is the second phase of cellular respiration which occurs within the

mitochondrial matrix. The CAC necessitates oxygen because it is employed by Acetyl CoA as

the mechanism of transportation around the cycle. The CAC implements the Acetyl CoA enzyme

produced in glycolysis as the primary intermediate for the entire cycle. Acetyl Co A approaches

entry to the cycle by way of the central metabolic pathway. In the mitochondria, the pyruvate

dehydrogenase enzyme changes the three carbon compound is changed into a two carbon

compound (acetate in the form of acetyl CoA) and CO2 is released; extra Hs are also formed,

and temporarily stored in a compound called NADH(University of Pennsylvania, n.d.). Without

this enzyme present the citric acid cycle could not occur, as Acetyl Co A is compulsory to the

cycle.

Glycerol, from fatty acids, can also enter the cycle through the central metabolic pathway

through the production of pyruvate. Amino acids enter the cycle at one of two pathways, either at

the central metabolic pathway or where Acetyl Co A cycles into the high energy carriers. At this

point it is changed as CO2 and H2O are given off along with other reduced coenzymes (NADH,

FADH2). These abridged products become substrates for the oxidative phosphorylation of the

Electron Transport Chain (ETC) within the in mitochondrias inner membrane space to

synthesize the bulk of ATP produced by cellular respiration,

The Citric Acid Cycle

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The Electron Transport Chain

The electron transport chain (ETC) is the final phase of cellular respiration and it has the

highest productivity when it comes to the production of ATP. ATP is formed as electrons are

transferred from NADH and FADH2 to O2 by a series of electron carriers over 10 redox centers

in four enzyme complexes (University of Houston, n.d.). This process is supported by

respiratory assemblages located within the inner membrane of mitochondria. This mechanism is

the bodys most efficient manufacturer of energy as the process of oxidation of NADH yields

three molecules of ATP and the oxidation of FADH2 yields two molecules of ATP. This occurs

in combination with pushing H+ out of mitochondrial matrix across inner membrane, as a result,

more molecules of ATP are fashioned as H+s return back into mitochondrial matrix (University
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of Houston, n.d.).
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Reference

East West Healing. (2012, February 14). Sucrose, Fructose & Glucose Part I & II [Video file].

Retrieved from East West Healing website: https://www.youtube.com/watch?

v=GY0LZcqtWX8

Nelson, T., Lucignani, G., & Atlas, S. (1986). Glucose-6-phosphatase activity in brain. Science,

2341128-1129.

Sawnson, P. D. (2014). Web Exclusives | Paul D. Swanson We Are What We Eat The Origins and

Current Legal Status of Natural and Organic Food Labels. Gastronomica.

Retrieved from http://www.gastronomica.org/we-are-what-we-eat/

Taylor, R. W., & Turnbull, D. M. (2005). Mitochondrial DNA Mutations in Human Disease.

Nature Reviews. Genetics, 6(5), 389402. doi:10.1038/nrg1606

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University of Houston. (n.d.). Oxidative Phosphorylation & Electron Transport. Retrieved from

http://www.uh.edu/dtu/07-Oxipho-1-07.htm

University of Pennsylvania. (n.d.). Chap. 4-6. ATP, glycogen, protein. Retrieved from

http://www.med.upenn.edu/biocbiop/faculty/vanderkooi/chap4-6.pdf