Regulation of metabolism on the

cellular levelVladimíra Kvasnicová

General Principles of Regulation

• catabolic / anabolic processes• last step of each regulation mechanism:

change of a concentration of an active enzyme (= regulatory or key enzyme)

• regulatory enzymes often allosteric enzymes catalyze higly exergonic reactions

(irreverzible) low concentration within a cell

I. Regulation on the organism level

1. signal transmission among cells(signal substances)

2. signal transsduction through the cell membrane

3. influence of enzyme activity: induction of a gene expression interconversion of existing enzymes

(phosphorylation / dephosphorylation)

II. Regulation on the cell level

1. compartmentalization of mtb pathways2. change of enzyme concentration

(on the level of synthesis of new enzyme )

3. change of enzyme activity(an existing enzyme is activated or inactivated)

1. Compartmentalization of mtb patways

• transport processes between compartments

• various enzyme distribution• various distribution of substrates and

products ( transport)• transport of coenzymes• subsequent processes are close to each

other

Compartmentalization of mtb pathways

The figure is found at http://fig.cox.miami.edu/~cmallery/150/proceuc/c7x7metazoan.jpg (May 2007)

Cytoplasm• glycolysis• gluconeogenesis (from oxaloacetate or glycerol)• metabolism of glycogen• pentose cycle• synthesis of fatty acids• synthesis of nonessential amino acids• transamination reactions • synthesis of urea (a part; only in the liver!)• synthesis of heme (a part)• metabolism of purine and pyrimidine

nucleotides

Mitochondrion

• pyruvate dehydrogenase complex (PDH)• initiation of gluconeogenesis -oxidation of fatty acids• synthesis of ketone bodies (only in the liver!) • oxidation deamination of glutamate • transamination reactions• citrate cycle• respiratory chain (inner mitochondrial membrane)• aerobic phosphorylation (inner mitoch.

membrane) • synthesis of heme (a part)• synthesis of urea (a part)

Endoplasmic Reticulum

Smooth ER• synthesis of triacylglycerols and phospholipids• elongation and desaturation of fatty acids• synthesis of steroids• biotransformation of xenobiotics• glucose-6-phosphatase

Rough ER• proteosynthesis

(translation and posttranslational modifications)

Golgi Apparatus

• posttranslational modification of proteins• protein sorting • export of proteins (formation of vesicules)

Ribosomes • proteosynthesis

Nucleus• replication and transcription of DNA• synthesis of RNA

Lysosomes

• hydrolysis of proteins, saccharides, lipids and nucleic acids

Peroxisomes

• oxidative reactions involving O2

• use of hydrogen peroxide• degradation of long chain FA (from C20)

2. Synthesis of new enzyme molecules:

• induction by substrate or repression by product(on the level of transcription)

examples:xenobiotics induction of cyt P450heme repression of delta-aminolevulate

synthase

3. Change of activity of an existing enzyme

a) in relation to an enzyme kinetics concentration of substrates ( Km) availability of coenzymes consumption of products pH changes substrate specificity - different Km

b) activation or inactivation of the enzyme• covalent modification of the enzymes

interconversion: phosphorylation/dephosphorylation) cleavage of an precursore (proenzyme, zymogen)

• modulation of activity by modulators (ligands): feed back inhibition cross regulation feed forward activation

3. Change of activity of an existing enzyme

Phosphorylation / dephosphorylation

• some enzymes are active in a phosphorylated form, some are inactive

• phosphorylation:protein kinasesmacroergic phosphate as a donor of the

phosphate (ATP!)

• dephosphorylationprotein phosphatase inorganic phosphate is the product!

The figure is found at: http://stallion.abac.peachnet.edu/sm/kmccrae/BIOL2050/Ch1-13/JpegArt1-13/05jpeg/05_jpeg_HTML/index.htm (December 2006)

Reversible covalent modification:

A)• phosphorylation by a protein kinase• dephosphorylation by a protein phosphatase

B)• phosphorylated enzyme is either active or inactive (different enzymes are influenced differently)

Modulators of enzyme activity(activators, inhibitors)

• isosteric modulation: competitive inhibition

• allosteric modulation:change of Km or Vmax

T-form (less active) or R-form (more active)

• important modulators: ATP / ADP