biosynthesis using amino acids: heme, active amines ......heme biosynthesis and degradation heme is...
TRANSCRIPT
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Asst. Prof. Dr. Altijana Hromic-Jahjefendic
SS2020
Biosynthesis using amino acids:
Heme, active amines & alkaloids
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Amino acids as biosynthetic precursors
• Biosynthesis of porphyrines
• Biosynthesis of physiologically active amines
• Biosynthesis of „secondary“ metabolites: alkaloids
• Biosynthesis of purine and pyrimidine bases
• Biosynthesis of naturally occurring antibiotics: penicillin
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Heme biosynthesis and degradation
Heme is an iron-containing tetrapyrrol
constitutes the essential prosthetic group of many
proteins such as hemoglobin, myoglobin and the various
cytochromes
Using radioactive labeling - all C- and N-atoms of the
tetrapyrrols are derived from acetate and glycine
partly in the mitochondrion and cytosol
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Initial reaction
condensation of glycine and succinyl-CoA to yield delta-aminolevulinic
acid (ALA)
in the mitochondrion
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Heme biosynthesis
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Enzymes and location of heme biosynthesis
Eight enzymes are involved in heme biosynthesis
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Regulation of heme biosynthesis two major sites for heme biosynthesis:
erythroid cells (85%)
liver (15%)
Biosynthesis in the liver - metabolic demand for heme dependend
In erythroid cells - biosynthesis is a one time event during maturation of reticulocytes into erythrocytes
heme production ceases upon maturation and the amount of hemoglobin formed
remains constant during the lifetime of the erythrocyte (ca. 120 days)
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Regulation of heme biosynthesis
in liver cells is largely due to feedback regulation of ALA
synthase by heme
in erythrocytes heme stimulates the expression of globin and
its biosynthetic enzymes in an „all switched on“ process
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Disorders of heme biosynthesis
Porphyrias - disorders caused by abnormalities in heme
biosynthesis
inherited or acquired and characterized by excessive
accumulation and excretion of porphyrins or their precursors
Inherited defects (any of the eight enzymes involved in heme
biosynthesis) can cause porphyrin-related disorders
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Disorders of heme biosynthesis
Porphyrins - deep red or purple color
Depending on their solubility - excreted in the urine and/or in
bile
Solubility - depends on the number of carboxylic side chains
some porphyrias may be associated with a deep red colouring of
the urine
Other symptoms: abdominal pain, constipation and neurological
disorders
Some individuals experience excessive growth of hairs in the
face and extremities (werewolf legend!)
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Inherited defects in heme biosynthesis
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Acute intermittent prophyria
most common inherited porphyria
individuals suffer from acute attacks of abdominal pain and
neurological dysfunction
Large amounts of delta-aminolevulinic acid and porphobilinogen
are exreted in the urine - red color
King George III (1738-1820)
During and after the attacks his urine had the color of port wine
Several other members of the family also suffered from the
disease (Mary Queen of Scots and Frederick the Great)
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Heme degradation
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Heme degradation
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Biosynthesis of physiologically active amines
Epinephrine, norepinephrine, dopamine, serotonin (5-
hydroxytryptamine),γ-aminobutyric acid (GABA) and histamine
neurotransmitters derived by decarboxylation from amino
acids
Sometimes hydroxylation
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Functions of physiologically active
amines
Epinephrine: activates muscle adenylate cyclase (glycogen
breakdown)
Dopamine: neurotransmitter (Parkinson’s Disease)
Serotonin: smooth muscle contraction
GABA: inhibitory neurotransmitter in the brain (30% of all
synapses)
Histamine: allergic responses/acid secretion in the stomach
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Decarboxylation of amino acid precursors - involves a
pyridoxalamine (PLP-) dependent reaction
To form active amines
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Biosynthesis of histamine and GABA
one step decarboxylation processes from glutamate and
histidine
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Biosynthesis of serotonine
hydroxylation of tryptophan
followed by the PLP-dependent decarboxylation
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Epinephrine, norepinephrine and
dopamine
called catechol amines
Production - depends largely on the expression of the
required enzymes in a given tissue
adrenal medulla – produces epinephrine
all the required enzymes for the production
Synthesis starts from tyrosine
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Biosynthesis of catechol amines
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Biosynthesis of alkaloids from amino acids
non-aromatic and aromatic amino acids
Alkaloids - non-peptidic and nonnucleosidic compounds
containing nitrogen
in higher plants, insects, amphibians and fungi
have a biological activity and used for pharmacological
purposes
In nature – act mediators of chemical communication
between organisms of the same or different species
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Non-aromatic amino acids as precursors of
alkaloids
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Aromatic amino acids as precursors of
alkaloids
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Isoquinoline alkaloids: Morphine & codeine
Morphine is produced by poppy plant
contained in the unripe seedpods
Cutting – white exudate appears; dried and collected (opium)
Raw opium contains between 10-15% morphine
inestimable value
reduce or abolish pain without causing a loss of consciousness
relieve coughs (codeine and derivatives), spasms, fevers and
diarrhea
Frequent and regular use leads to addiction
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Heroin
morphine’s addictive properties
Synthesis of diacetylmorphine
hailed as a safe compound and it was even thought that it
could be used to treat morphine addiction...
1898 with the brand name heroin
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Biosynthesis of secondary compounds
aromatic amino acids are „primary“ compounds
Metabolites beyond - „secondary“ compounds
Metabolism - „secondary metabolism“
not secondary in their importance
Some play essential roles in herbivore and pathogen defense in plants
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Aromatic amino acids are precursors for
„secondary plant metabolites“
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Importance of plant metabolites!
Coumarins - significant in the treatment of cancer and is
used in the treatment of prostate cancer, renal cell carcinoma
and leukemia
good maintenance therapy in case of melanoma and also
found to inhibit the spread of tumors
Betalains - protection from the harmful effects of
ultraviolet radiation in the ice plant
roles in plant physiology and visual attraction for pollinators
and seed dispersers
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Importance of plant metabolites!
Anthocyanins - acting as antioxidants and fighting free
radicals
offer anti-inflammatory, anti-viral, and anti-cancer benefits
Lignins - form key structural materials in the support
tissues of vascular plants and some algae
important in the formation of cell walls, especially in wood
and bark
plays a crucial part in conducting water in plant stems
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Biosynthesis of purines & pyrimidines
sythesized from the amino acids aspartate, glutamine and
glycine
+ formiate and carbonate
synthesis of purines is more complicated than that of
pyrimidines
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Summary
Heme biosynthesis
Heme degradation and regulation
Disorders of heme biosynthesis
Biosynthesis of active amines
Biosynthesis of alkaloids
Biosynthesis of secondary compunds
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Quiz 1
Thursday 12.03.2020
10:00
Be on time
First 2 chapters (fatty acids, terpens and steroids/ amino
acids)