5. Chemical Reactions in the Metabolism


1. The most significant chemical reactions
2. The principles of regulation of metabolic pathways


The most significant chemical reactions

Metabolic pathways in human organism form vast network of more or less interconnected reactions that often share common intermediate products. Chemical conversions, which occur during the chemical reactions, can be divided according to the general mechanism, shared by all substances undergoing that particular reaction. For example, decarboxylation reactions involve splitting off a CO2 molecule from the carboxyl group and its substrates include various carboxylic acids.

In this subchapter, we will speak about the most important types of chemical reactions with typical examples taken from human metabolic pathways.

Alcohols, carbonyl compounds and carboxylic acids

Alcohols, carbonyl compounds and carboxylic acids form an important group of substances involved in many chemical reactions of intermediate metabolism.

Alcohols are characterized by the presence of OH- functional group. Depending on the number of these groups in the molecule, alcohols can by mono-, di- or polyhydric. Another division is based on the nature of a carbon atom to which an OH- group is attached: primary (R-CH2-OH), secondary (R1-CH(OH)-R2) and tertiary (C-R1R2R3(OH)) alcohols.

Aldehydes and ketones together, for a group of carbonyl compounds. Their functional groups are –CHO and C=O, respectively.

Carboxylic acids, characterised by the presence of –COOH group, and their derivatives are probably the most important members of this group of substances.

Alcohols, carbonyl compounds and carboxylic acids participate in many reactions – among the most significant are:

1) The formation of anions and acyls, derived from carboxylic acids

2) Dehydrogenations and hydrogenations (oxidations and reductions)

3) Esterifications

1) The formation of anions and acyls, derived from carboxylic acids

Carboxyl group is capable of dissociation, the extent of which, for a particular acid, is expressed by dissociation constant. In general, carboxylic acids belong to weak acids, which means that they dissociate only partially. The resulting anion (with -COO group) is termed acetate.

After splitting off the OH- group from carboxyl an acyl is formed.

2) Dehydrogenations and hydrogenations (oxidations and reductions)

Dehydrogenation is a chemical reaction leading to the elimination of –H atom from the molecules. The hydrogen atom obtained in this process can be subsequently used to create a proton gradient across the mitochondrial membrane in order to gain energy (ATP). The incorporation of the hydrogen into the molecule is termed hydrogenation. Hydrogenations and dehydrogenations occur during:

a) The oxidation of simple bonds to double bonds

b) The reciprocal conversions of alcohols – carbonyl compounds – carboxylic acids

a) The oxidation of simple bonds to double bonds

The general reaction scheme is as follows:

-CH2-CH2– ↔ -CH=CH- + 2H+ + 2e

Such reactions are abundant in Krebs cycle, β-oxidation of fatty acids or desaturation reactions (producing unsaturated fatty acids).

b) The reciprocal conversions of alcohols – carbonyl compounds – carboxylic acids

This threesome of organic compounds forms a series that differ in the degree of oxidation (or reduction). General scheme of their interconversion is as follows (conversion towards the carbonyl compound and carboxylic acid is oxidation, in opposite direction it is a reduction):

1. Primary alcohol ↔ aldehyde ↔ carboxylic acid


2. Secondary alcohol ↔ ketone

R1-CH(OH)-R2 ↔ R1-CO-R2

3. Tertiary alcohol – cannot be oxidised

As an example of oxidation, we can take the conversion of glycerol-3-phosphate to dihydroxyacetone phosphate (DHA-P), with FAD as a cofactor, through which a glycerol enters the metabolic pathways of glycolysis or gluconeogenesis (depending on the actual needs of the organism).

3) Esterification

Esterification is a reaction between carboxylic acid and alcohol, creating an ester and a water molecule:

R1-OH + R-COOH → R1O-(C=O)-R + H2O

The most important carboxylic acids and derived anions and acetyls are summarised in the following tables:

1) Saturated monocarboxylic acids
C Systematic name Common name Latin name Acyl Anion
1 Methanoic Formic ac. formicum Formyl Formate
2 Ethanoic Acetic ac. aceticum Acetyl Acetate
3 Propanoic Propionic ac. propionicum Propionyl Propionate
4 Butanoic Butyric ac. butyricum Butyryl  Butyrate
5 Pentanoic Valeric ac. valericum Valeryl Valerate
12 Dodecanoic Lauric ac. lauricum Lauryl Laurate
16 Hexadecanoic Palmitic ac. palmiticum Palmitoyl Palmitate
18 Octadecanoic Stearic ac. stearicum Stearoyl Stearate
2) Saturated dicarboxylic acids
C Systematic name Common name Latin name Acyl Anion
2 Ethanedioic oxalic ac. oxalicum Oxalyl Oxalate
3 Propanedioic Malonic ac. malonicum Malonyl Malonate
4 Butanedioic Succinic ac. succinicum Succinyl Succinate
5 Pentanedioic Glutaric ac. glutaricum Glutaryl Glutarate
6 Hexanedioic Adipic ac. adipicum Adipoyl Adipate
3) Unsaturated monocarboxylic acids
C Systematic name Common name Latin name Acyl Anion
18:1 cis- octadec-9-enoic Oleic ac. oleicum Oleoyl Oleate
18:2 (ω-6) cis,cis- octadeca-9,12-dienoic Linoleic ac.linoleicum Linoloyl Linolate
18:3 (ω-3) cis,cis,cis- octadeca-9,12,15-trienoic Linolenic ac.linolenicum Linolenoyl Linolenate
20:4 (ω-6) cis,cis,cis,cis- eicosa-5,8,11,14-tetraenoic Arachidonic ac. arachidonicum Arachidonyl Arachidonate
4) Unsaturated dicarboxylic acids
C Systematic name Common name Latin name Acyl Anion
4 cis- butenedioic Maleic ac. maleicum Maleinyl Maleinate
4 trans- butenedioic Fumaric ac. fumaricum Fumaroyl Fumarate
5) Derivatives of carboxylic acids
C Systematic name Common name Latin name Acyl Anion
3 2-oxopropanoic Pyruvic ac. pyruvicum Pyruvyl pyruvate
3 2-hydroxypropanoic Lactic ac. lacticum Lactoyl Lactate
4 3-oxobutanoic Acetoacetic Acetoacetyl Acetoacetate
4 3-hydroxybutanoic β-hydroxybutyric β-hydroxybutyrate
4 hydroxybutanedioic Malic ac. malicum Maloyl Malate
4 oxobutanedioic Oxaloacetic Oxalacetate
5 2-oxopentanedioic α-ketoglutaric α-ketoglutaryl (2-oxoglutaryl) α-ketoglutarate (2-oxoglutarate)
6 2-hydroxypropane-1,2,3-tricarboxylic Citric ac. citricum Citrate

Hydroxy acids and oxo acids

A mutual conversion of hydroxy acids (containing, apart from –COOH group, -OH group as well, replacing one of the hydrogen atoms in the chain) and oxo acids (also called keto acids, which contain both –COOH and =O group replacing one of the hydrogen atoms in the chain) is a common phenomenon of metabolic pathways. Hydroxy acids oxidise to oxoacids or vice versa, oxoacids reduce to hydroxy acids as depicted in the following examples:

Another phenomenon occurring in metabolism is keto-enol tautomerism that refers to a chemical equilibrium between two forms of organic compounds: keto– (or oxo-) form, containing oxygen bound by double bond (=O) and enol form, containing double bond between two carbon atoms together with –OH group attached to one of them (-C=C-OH). Their interconversion involves the movement of alpha hydrogen (or proton) and the shifting of bonding electrons (seen a as shift of double and its adjacent single bond).

Amino acids and oxo acids

Amino and oxoacids represent a substitution derivatives of carboxylic acids. Molecules of amino acids contain the –COOH group together with -NH2 group whereas oxoacids have =O group. When interconverting, these two groups exchange the -NH2 and =O groups. There exist two main types of these reactions:

1) Transaminations

2) Oxidative deaminations

1) Transaminations

In this type of reactions, amino acid acts as a -NH2 group donor that is accepted by oxoacid. The oxoacids converts to amino acid and amino acids becomes oxoacid.

AA1 + OxoA2 ↔ OxoA1 + AA2

2) Oxidative deamination

In this reaction, an oxoacids is formed by elimination the -NH2 group from amino acids. NH2– is released as an ammonia (NH3). Oxidative deaminations are important reactions through which amino acids begin their degradation process. They mainly occur in liver and the produced ammonia enters the process of urea synthesis.

This reaction is catalysed by glutamate dehydrogenase.

Decarboxylations and carboxylations

Decarboxylation is a chemical reaction that involves the elimination of the whole carboxy group (released as a molecule of CO2) and its replacement with proton. It is a part of several metabolic pathways:

1) The conversion of amino acids to biogenic amines (e.g. during the synthesis of many neurotransmitters)

Synteza katecholaminu ENG-01

2) Dehydrogenations of 2-oxoacids – pyruvate dehydrogenase reaction and two reactions of Krebs cycle

Carboxylation takes a reversed course, it involves an incorporation of –COOH group into the molecule, for example:

1) Fatty acids synthesis

2) Gluconeogenesis


The principles of regulation of metabolic pathways

Regulatory reactions of metabolic pathways are usually localized somewhere near the beginning of the particular pathway – very often they are the first irreversible reaction. The reason is a tendency to reduce the waste of resources and unnecessary production of intermediates (that would occur, when the pathway would not be halted at the beginning but after several steps).

The regulatory enzyme is often present at low concentration (lower compared to the concentrations of other enzymes involved in the pathway) that limits its function. Furthermore, the enzyme usually belongs to the group of allosteric enzyme, operating according to “all-or-none” principle. The existence of a concentration limit (above which the reaction soon reaches the maximum speed but below which it almost does not occur) is quite advantageous for regulation.

Regulation of metabolic pathways is based on, as is also the case of other regulated processes within the body, the principle of feedback. The intermediates or the end products of reactions affect the course of the reaction.

1) Negative feedback

The deviation from a certain value (set point) triggers a chain of reaction, which brings the system back to its previous state. Negative feedback is therefore the source of the stability (by constantly bringing the system back to the set point) and is the basic regulatory mechanism in almost all metabolic processes.

As an example we can take an enzyme ALA-synthase I (a regulatory enzyme of heme synthesis, localised in liver). When the concentration of the end product (heme) is high, it slows (through negative feedback) the whole pathway down.

2) Positive feedback

The deviation from the value of set point, leads in this case to the chain of reactions that further deepen the deviation. The system is at risk from the creation of vicious circle, where each further increase of deviation speeds up the whole process, until the instability of the system reaches the point where it collapses.

The widely known example of positive feedback in our bodies is represented by oxytocin. Oxytocin is a peptide hormone produced in hypothalamic nuclei that (apart from other functions) causes the contraction of smooth muscles of uterus during delivery. Every contraction activates mechanoreceptors lying in the uterus wall, which acts as a stimulus for further secretion of oxytocin. That is why its effect increases until both baby and placenta are born and the pressure in the uterus drops.

Regulatory step is affected by:

1) Change of absolute concentration of enzyme (the amount of the enzyme)

It can be regulation through the changes in transcription and translation of the particular enzyme. Induction activates and repression inhibits a gene expression. Example is the substrate induction, when the synthesis of a certain gene is induced by the presence of its substrate.

2) Modulation of the activity of an already existing enzyme (the activity of enzyme)

The activity of enzyme can be affected by:

a) Presence of activator or inhibitors

b) Covalent modification of enzyme molecule (phosphorylations / dephosphorylation, changing proenzymes into the active forms, …)


Subchapter Author: Petra Lavríková