View source for 16. Synthesis of biologically active molecules from amino acids

== Learning objectives ==

* Which proteins contain porphyrins?
* Which substrates are required for porphyrin synthesis?
* What are porphyrias?
* Which porphyria is most common?
* How is heme degraded?
* What is the function of creatine?
* Which substrates are required for creatine synthesis?
* Which substrates are required for glutathione synthesis?
* Describe the synthesis of catecholamines
* Describe the synthesis of GABA
* Describe the synthesis of serotonin
* Describe the synthesis of histamine
* Which substrates are required for spermine and spermidine synthesis?
* Describe the synthesis of NO

== Porphyrin and heme synthesis ==
Porphyrins are circular molecules which consist of four porphobilinogen molecules. Many proteins contain porphyrins, including haemoglobin, myoglobin, cytochromes, and NO-activated guanylyl cyclase.

The synthesis of porphyrins require succinyl-CoA and glycine.

Heme is the functional group in haemoglobin which to iron. As a porphyrin it is synthesised from succinyl-CoA and glycine. 8 Succinyl-CoA are combined and go through many reactions, where they become a type of molecule called porphyrins, until they end up as heme.

Porphyrias are genetic diseases where there are defects in one of the enzymes required for porphyria synthesis. The most common porphyria is ''acute intermittent porphyria'', which is due to ''porphobilinogen deaminase'' deficiency.

Heme is degraded to biliverdin and CO by ''heme oxidase''. CO is a vasodilator and a neurotransmitter, but it is toxic in high concentrations. Biliverdin is reduced to bilirubin, an antioxidant and an important component of bile.

Bilirubin then enters a pathway to end up as urobilin as stercobilin, which are excreted in urine and feces, respectively. Jaundice is the condition in which biliverdin in the blood increases, and the skin turns yellow. More about this in physiology.

== Creatine ==
Creatine is an organic acid which acts as an important short-term energy source in muscle. Creatine stores high-energy phosphate groups in the form of phosphocreatine. During hard exercise, phosphocreatine can regenerate ATP by losing its phosphate group.

Creatine itself is synthesised from glycine and arginine, and adoMet is required. Phosphocreatine is formed from creatine and ATP by ''creatine kinase''.

== Glutathione ==
Glutathione was already introduced in topic 1, but as a quick reminder, its the most important antioxidant in the body.

Glutathione itself is synthesized from glutamate, cysteine and glycine. The enzyme which consumes glutathione to reduce peroxides is called ''glutathione peroxidase''.

== Neurotransmitters ==
Tyrosine is the precursor of ''catecholamines'', three biological molecules which are both neurotransmitters and hormones. They are dopamine, norepinephrine and epinephrine.

Tyrosine is converted into dopa by ''tyrosine hydroxylase'', which requires tetrahydrobiopterin. ''Aromatic amino acid decarboxylase'' converts dopa into dopamine, which requires PLP. Dopamine is converted to norepinephrine by ''dopamine β-hydroxylase.'' This enzyme requires ascorbate (vitamin C), which is important to remember. Norepinephrine is converted to epinephrine by ''phenylethanolamine N-methyltransferase'', which requires adoMet.

In Parkinson disease, dopamine is underproduced. The treatment is supplement of DOPA, the direct precursor of dopamine. Dopamine is not given because it cannot cross the blood-brain barrier, however DOPA can. Schizophrenia is caused by overproduction of dopamine.

GABA (gamma-aminobutyrate) is an inhibitory neurotransmitter. It’s synthesised from glutamate by ''glutamate decarboxylase'', which requires PLP. Epileptic seizures are caused by underproduction of GABA.

Serotonin is another inhibitory neurotransmitter. It is synthesized from tryptophan. Tryptophan is converted to 5-hydroxytryptophan (5-HT) by ''tryptophan hydroxylase'', which requires tetrahydrobiopterin. 5-HT is converted to serotonin by ''aromatic amino acid decarboxylase'', which requires PLP.

== Histamine ==
Histamine is a powerful vasodilator. It is released in allergic responses. It also stimulates acid secretion in the stomach. It is synthesized from histidine by ''histidine decarboxylase'', which requires PLP.

== Spermine and spermidine ==
Spermine and spermidine are polyamines which are involved in DNA packaging. They are synthesized from methionine and ornithine.

== Nitric oxide ==
Nitric oxide (NO) is an important biomolecule. It is synthesised from arginine by ''NO synthase'', an enzyme which we’ll return to in later chapters.

== Summary ==

* Which proteins contain porphyrins?
** Haemoglobin, myoglobin, cytochromes, and NO-activated guanylyl cyclase
* Which substrates are required for porphyrin synthesis?
** Succinyl-CoA and glycine
* What are porphyrias?
** Porphyrias are genetic diseases where there are defects in one of the enzymes required for porphyria synthesis.
* Which porphyria is most common?
** Acute intermittent porphyria
* How is heme degraded?
** Heme is degraded to biliverdin and CO by ''heme oxidase''. Biliverdin is then reduced to bilirubin
* What is the function of creatine?
** Creatine acts as a short-term energy store in muscles. It is stored in the phosphocreatine form, which can regenerate ATP from ADP when needed
* Which substrates are required for creatine synthesis?
** Glycine and arginine, and adoMet is required
* Which substrates are required for glutathione synthesis?
** Glutamate, cysteine and glycine
* Describe the synthesis of catecholamines
** Tyrosine is converted into dopa by ''tyrosine hydroxylase''
** ''Aromatic amino acid decarboxylase'' converts dopa into dopamine.
** Dopamine is converted to norepinephrine by ''dopamine β-hydroxylase.'' This enzyme requires ascorbate (vitamin C).
** Norepinephrine is converted to epinephrine which requires adoMet.
* Describe the synthesis of GABA
** It’s synthesised from glutamate by ''glutamate decarboxylase'', which requires PLP.
* Describe the synthesis of serotonin
** Tryptophan is converted to 5-hydroxytryptophan (5-HT) by ''tryptophan hydroxylase''.
** 5-HT is converted to serotonin by ''aromatic amino acid decarboxylase''.
* Describe the synthesis of histamine
** It is synthesized from histidine by ''histidine decarboxylase''
* Which substrates are required for spermine and spermidine synthesis?
** Methionine and ornithine.
* Describe the synthesis of NO
** It is synthesised from arginine by ''NO synthase''

[[Category:Biochemistry 1 lectures]]