Amino Acid Metabolism Series 4 PDF

FATE OF CARBON SKELETONS AFTER THE REMOVAL OF NITROGEN After the removal of nitrogen from amino acids, their carbon skeletons can give rise to intermediates of glycolysis or the TCA cycle either directly or via a series of degradation reactions – and so amino acids are designated glucogenic or keto...

FATE OF CARBON SKELETONS AFTER THE REMOVAL OF NITROGEN After the removal of nitrogen from amino acids, their carbon skeletons can give rise to intermediates of glycolysis or the TCA cycle either directly or via a series of degradation reactions – and so amino acids are designated glucogenic or ketogenic FATE OF CARBON SKELETONS AFTER THE REMOVAL OF NITROGEN Amino acids that are degraded to pyruvate or citric acid cycle intermediates are called glucogenic because they can directly supply the pathway of gluconeogenesis Those that form acetyl CoA or acetoacetate can contribute to the formation of fatty acids or ketone bodies and are called ketogenic Some amino acids are both glucogenic and ketogenic because different parts of their carbon chains form different products e.g. phenylalanine, tyrosine, Lysine degradation A ketogenic amino acid Saccharophine dehydrogenase (LYS1) – the enzyme that is important in this NAPD+, glutamate Degradation of ketogenic lysine - Saccharophine dehydrogenase Phenylalanine degradation and associated clinical implications An example of an amino acid that is both glucogenic and ketogenic is provided in phenylalanine (and tyrosine) whose end products are fumerate and acetoacetate  The disease is caused by a mutation in the gene that encodes phenylalanine hydroxylase Phenylalanine hydroxylase is a mixed function oxidase which donates one O to form water and the other to PHENYLKETO form tyrosine using molecular oxygen (O2) The hydrogen donor is coenzyme tetrahydrobiopterin NURIA ( BH4) which is itself oxidized to dihydrobiopterin - one of the most common (BH2). BH4 is regenerated through reduction by NADH in a reaction catalyzed by dihydrobiopteridine disorders of amino acid reductase metabolism is phenylketonuria (PKU).  PHENYLKETON URIA Affected individuals are unable to convert dietary phenylalanine to tyrosine so the blood of children with this disease contain high levels of phenylalanine and low levels of tyrosine Instead of being converted to tyrosine, phenylalanine is metabolized to phenylpyruvate Elevated levels of pheylpyruvate and its derivatives inhibit brain development Newborns are routinely screened for PKU by testing for elevated levels of phenylpyruvate in the urine or of phenylalanine in the blood during the  ALKAPTONURI A It is an inborn error of metabolism: a genetic disease caused by a lack of the enzyme homogentisate dioxygenase(HGD). Without HGD, patients cannot break down protein to amino acids, such as tyrosine and phenylalanine, which causes a build up of homogentisic acid(HGA)in the bones, cartilage and urine. Alkaptonuria is characterized by the presence of black urine, ochronosis (black bones and cartilage) and a degenerative arthritis of the joints. ALKAPTONURIA A deficiency of α-keto acid dehydrogenase is the most common enzyme abnormality in branched chain amino acid catabolism  OTHER DISEASES OF AMINO ACID METABOLISM 1. CYSTINURIA Occurs if there is a defect in kidney transport of cysteine and the basic amino acids Cysteine accumulates in the blood and oxidizes to cystine producing the condition Cystinuria Cystine has a low solubility and forms calculi Patients suffering from cystinuria drink large amounts of water to dissolve these stones or are given compounds that react with cysteine to form soluble derivatives OTHER DISEASES OF AMINO ACID METABOLISM 2. GYRATE ATROPHY A defect in ornithine transaminase activity causes the metabolic disease Gyrate atrophy of the choroid and retina of the eyes The affected gene OAT is on chromosome 10 Gyrate atrophy leads to tunnel vision and later to blindness The progress of the disorder can be slowed by restricting dietary intake of arginine or by the administration of pyridoxine OTHER DISEASES OF AMINO ACID METABOLISM 2. NONKETOTIC HYPERGLYCINEMIA (GLYCINE ENCEPHALOPATHY) Defects in the enzyme complex that catalyzes glycine cleavage leads to the accumulation of large amounts of glycine in body fluids Most individuals with this disorder have severe metal deficiencies and die at infancy The severity of the disease indicates the crucial importance of the glycine cleavage system Amino acids in the body Amino acids are used in the synthesis of very important compounds Heme synthesis Glycine together with TCA cycle intermediate succinyl CoA are the starting materials in the heme synthesis which involves the build up tetrapyrolle (porphyrin) ring structure and ends with the incorporation of the Fe atom Deficiencies involving a number of enzymes in the pathway give rise to a class of diseases called porphyrias  Creatine synthesis Creatine is synthesised from arginine and glycine The catabolic product of creatine is creatinine which is excreted in the urine The amount of creatinine excreted in the urine over a 24 h period is used to determine glomerular function Thus creatinine is measured to access renal function Note the transmethylation reaction by S- adenosylmethionine) Catecholamines synthesis Catecholamines are synthesized from phenylalanine hydroxylation to tyrosine Catecholamines include: i) L-Dopa (L-Dihydroxyphenylalanine); ii) Norepinephrine (Noradrenalin) iii) Epinephrine (Adrenalin) Catecholamines synthesis - clinical implications Tyrosine is hydroxylated to Dopa which is further metabolized to different products depending on the tissue Dopamine: produced from Dopa through a decarboxylation. It acts as a neurotransmitter in specific regions of the brain. A decreased production results in Parkinson’s disease Catecholamines synthesis - clinical implications Melanin results from oxidation of Dopa by tyrosinase in melanocytes This produces dopaquinone and other derivatives of Dopa which condense form dark pigment, melanin which is concentrated in skin, hair, eye and brain Defects in the pathway melanin synthesis result in albinism Catecholamines synthesis – “fight or flight hormones” Norepinephrine – is a neurotransmitter that functions in the human brain Epinephrine- is a hormone produced in by both the adrenal glands and certain neurons It plays an important role in the fight-or-flight response by increasing blood flow to the muscles, output of the heart, pupil dilation, and blood sugar Epinephrine does this by its effects on alpha and beta receptors Tyrosine metabolism products The thyroid gland produces iodinated derivatives of tyrosine: i) Triiodothyronine (T3), and ii) Tetraiodothyronine(T4)  Tryptophan metabolism products The nicotinamide moiety of NAD(P)is derived from tryptophan Serotonin (5-hydroxytryptamine) is a neurotransmitter outside the central nervous system. It is a stimulator of smooth muscle contraction and also a vasoconstrictor Melatonin is produced by the pineal gland during the dark phase of the daily cycle and is involved in maintenance of daily seasonal rhythms Neurotransmitters from glutamine Brain neurons can synthesize glutamate through hydrolysis of glutamine by glutaminase Glutamate is an excitatory neurotransmitter The decarboxylation of glutamate by glutamate decarboxylase produces γ- aminobutyric acid (GABA) which is an inhibitory neurotransmitter