Catabolism of Amino Acids

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1

Catabolism of amino acid skeleton

-->Involves the removal of the α-amino group, followed by the breakdown of the resulting carbon skeletons

2

2 Molecules that are categorized as the basis ketogenic amino acids

1)Acetyl CoA
2)Acetoacetyl CoA

3

5 Molecules that are catoragized as the basis of gluconeogennic amino acids

1)Pyruvate
2)OAA
3)Fumarate
4)α-KG
5)Succinyl-CoA

4

Classification of AA

1)Ketogenic Amino Acids (**Leucine & Lysine**)
2)Gluconeogenic & Ketogenic Amino Acids
(***Larger Amino Acids, including Isoleucine, Phenylalanine, Tyrptophan, & Tyrosine)
3)Ketogenic AA
--->All other AA's

5

Gluconeogenic AA

-->Amino acids whos catabolism yields pyruvate or one of the intermediates of the citric acid cycle
-->Substrates for gluconeogenesis (which can give rise to the net formation of glucose in the LIVER & KIDNEY)

6

Ketogenic AA

-->AA whose catabolism yields either acetoacetate or one of the precursors

7

Picture of Gluconeogenic & Ketoneogenic Amino Acids

-->See Slide #4 & 5

8

Amino Acids that form OAA (see slide for details

-->Asparagine --> Aspartate --> OAA:
1)First Rxn. is catalyzed by asparaginase
2)Second Rxn is a transanimation reaction

9

Amino Acids that form α-KG

-->Glutamine --> Glutamate --> α-KG:
1)First Rxn is catalyzed by Glutaminase
2)Second Rxn is catalyzed by glutamate dehydrogenase
--
-->Proline --> Glutatmate (Catalyzed by glutamate dehydrogenase)
--
Arginine --> Ornithine --> α-KG:
1)First rxn. is catalyzed by Arginase
--
Histidine --> N-Forminoglutamate (FIGlu):
1)FIGIu donates its forminino group to tetrahydrofolate, leaving glutamate

10

Amino Acids that form Pyruvate

1>)Theronine --> Glycine --> --> Pyruvate
2)Glycine: Has 2 fates
-->Converted to SERINE by the addition of a methylene group from N5N10-methlenetretrhydrofolate
-->Oxidized to CO2 & NH4+
3)Serine has 2 fates:
-->Converted to a GLYCINE & a N5N10 methleneteetrahydrofolate
-->Converted to a PYRUVATE by serine dehydratase
4)Alanine --> Pyruvate loses amino group by ALT
5)Cysteine:
***CYS-TINE is reduced to Cysteine (uses NADH)
-->***Cysteine undergoes a desulfuration to yeild pyruvate

11

Amino Acids that form fumarate

-->***Phenylalanine and tyrosine***: Hydroxylation of phenylalanine leads to the formation of tyrosine This reaction, catalyzed by ***phenylalanine hydroxylase***
-->It is the first reaction in the catabolism of phenylalanine. Thus, the metabolism of phenylalanine and tyrosine merge, leading ultimately to the formation of ***fumarate and acetoacetate***(IMPORTANT!!!)
-->Phenylalanine and tyrosine are,
therefore both glucogenic
and ketogenic amino acid

12

AA's that form succinyl CoA

1)Valine & Isoleucine --> Are BCAA AA's that yield succinyl-CoA
2)Theronine --> *α-KG* --> Propionyl CoA OR Theoronine --> *Pyruvate*

13

Methoinine

-->Is formed from ***succinyl-CoA***
-->Methionine is converted to S-adenosylmethionine (SAM), which is a ***methyl donor***
1)By donating its methyl group during methylation reactions, SAM becomes S-adenosylhomocysteine (SAH), which forms ***Homocysteine***(a metabolite associated with cardivascular/atherosclerotic vascular diesease)

14

Regulation of Methionine (

*See notes***)**-->Based on the amount of ***Methionine & Cysteine***
-->If Methionine & Cysteine are HIGH:
1)SAM will accumulate, which will act as a POSITIVE EFFECTOR OF CYSTATHIONINE SYNTHASE
2)Leads to the Production of Cysteine & α-keto butyrate, both of which are GLUCOGENIC

15

AA's that form acetyle CoA or Acetoacetyl CoA (Acetoacetate)

*w/o pyruvate serving as an intermediate**1)Leucine
2)Isoleucine
3)Tryptophan
4)Lysine

16

Phenylalanine & Tyrosine

-->Alos give rise to **acetoacetate*** via the formation of two important molecules:
1)***Homogenistic Acid***
2)Fumarate

17

Features of the Catobolism of the BCAA's

-->Steps of the degredation of BCAA's:
1)All branched chain AA's are converted to ***α-keto acids*** in the skeletal muscle & other extrahepatic tissues
a)Catalyzed by α-keto dehydrogenases

2)All resulting α-keto acid are transported to the LIVER, where they are oxidatively decarboxylated by a ***mitochondrial enzyme complex***
a)Complex resembles the pyruvate dehydrongenase complex in STRUCTURE, CONENZYME REQUIREMENTS, & REACTION MECHANISM

3)The remaining reactions DIFFER fro the three amino acids:

a)Valine --> Forms ***propoinyl CoA***, which is converted into succinyl-CoA (***gluconeogenic***)
b)Isoleucine --> Forms both ***propionyl CoA & Acetyl CoA*** (***gluconeogenic & ketogenic***)
c)Leucine forms ***acetoacetate*** (***ketogenic)
--
NOTE: Deficiencies in the ***α-keto acid dehydrogenases***are responsible for ***maple syrup urine disease***

18

Biosynthesis of Non-Essential Amino Aicds

-->See slide #15

19

Aspartate

-->Is converted into ***Asparagine*** by Asparagine Synthase via a transanimation reaction
1)Asparagine Synthase catalyses the reaction btwn. aspartate --> Asparagine
2)Asparinase catalyzes the rxn in the conversion of aspartate to asparigine
-->***Aspariginase** has been used in cases of adult leukemia where the malignant cells have lost the ability to synthesize asparagine
-->Since cancer cells depend on asparagine from the blood, the injected asparaginase destroys asparagine in the blood -->Depriving cancer cells of an essential nutrient

20

Serine

-->Is formed from the oxidation of the α-hydroxyl group of ***3-phosphoglycerate*** to an oxo acid
-->The oxo acid is ***transanimated & dephosphorylated*** to serine

21

Glycine

-->Can be derived from SERINE, caatalyzed by serine hydrroxy methyltransferase

22

Proline

-->Can be derived from PROLINE by cyclization & reduction

23

Cysteine (Non-essential AA)

-->Is formed from ***methionine***, which is NUTRIONALLY ESSENTIAL
-->Once methionine is converted to homocysteine, the ***conversion of cysteine & homoserine***)

24

Tyrosoine

-->Is derived from ***phenylalanine***
-->Catalyzed by phenylalanine hydroxylase
-->Requires ***BH4***(tetrahydrobiopterin)

25

Conversion of Amino Acids to Specialized Products (See Flow Chart)

-->See slides for details

26

Features of Pheylalanine & Tyrosine

-->Phenylalanine is converted to tyrosine and then finally to fumarate and acetoacetate
-->***Fumarate*** enters into the TCA cycle
-->***Acetoacetate*** is a ketone body and is oxidized to yield energy
-->Deficiencies of metabolizing enzymes leads to various disorders

27

General Features for Phenylketonuria (PKU)

-->Can be divided into 2 major types:
1)Classical PKU (***Deficiency in phenylhydroxylase)
2)Nonclassical PKU (***Deficiency of dihydropterine reductase***)

28

Requirements of Phe --> Tyrosine

-->Monooxygenase Rxn requiring:
1)Molecular O2
2)***Tetrahydrobiopterin (BH4)
(***also required for tyrosine & tryptophan hydroxylase reactions)
-->Consequences:
1)Accumulated Phe in the blood (*hyperphnylalanininemia*)
2)Mental Retardation (if left untreated)
3)Elevated Phenylacetate in the urine

29

Tetrahydrobiopterin

-->A cofactor of phenylalanine that becomes oxidized to ***dihydrobiopeterin***(BH2) during the reaction
-->***Dihydrobiopeterin Reductase*** is an NADH-dependent enzyme that reduces BH2 back into BH4

30

Diagnosis of PKU

-->Use newborn screening (via HPLC-based tests or Guthrie test (where blood sample is obtained via heel prick method; repeat after 2 weeks)
-->Ethnicity: Common in people of European ancestry, with highest freq. in Britan & Ireland
1)Less common in other racial groups

31

Guthrie Bacterial Inhibition Test

-->Test in which phenylketonuric blood (NOT the blood of normal individuals) supports the growth of phenylalanine-dependent bacterial strain

32

Disease Presentation of PKU in untreated children

1)***Albinism***(excessively fair hair & skin, hypopigmentation, eczema)
2)***musty or mousy order*** to the baby's seat & urine (DUE TO PHENYLACETATE, PHENYLPYRUVATE, & PHENETHALAMINE)

33

Newborn screening of PKU

--->MANDATORY IN THE US, b/c early detection & treatment prevents the detection of neurological problems, seizures, & mental retardation

34

Treatment of PKU

-->Special diet ***low in Phe*** for at least the first 16 years of their lives
1)Must severly restrict or eliminate foods HIGH in Phe (***meat, chicken, fish, eggs, nuts, chees, legumes, cow's milk, & other DIARY products)
2)***Aspartme***(artificial sweatner; N-aspartyl-phenylalanine methlester) is hazardous to the patient's health
-->Supplementary infant formulas are used b/c Phe is an ESSENTIAL AA (ex.***TYROSINE must be supplemented***)

35

Features of Maternal PKU

-->Expecting mothers that have PKU must maintain low-Phe levels before & during pregnancy b/c children of phenylketonuric children are mentally retarded (***esp. during 8-10th week of gestation)
1)Lack of maintenance of low PKU results in babiees with congenital heart disease, growth retardation, microcephaly, & mental retardation

36

Reason why PKU patients develop mental retardation

-->Phe is a ***large neutral AA (LNAA) (Ex. tyrosine, leucine, isoleucine, & valine)
-->LNAA's ***competitively*** saturated the large neutral amino acid transporter (LNAAT)
1)Resulting in excess levels of Phe causing a decrease in the levels of other LNAA's in the brain
2)Due to the decr. in other AA's necessary for neurotransmitter syn., Phe buildup, leading to maldevelopment of the brain --> ***mental retardation***

37

Alkaptonuria ("Black Urine Disease")

-->An autosomal recessive disorder due to a deficiency in the homogentisate oxidase enzyme
-->High incidence in ***slovakia & the dominican republic***
-->Major consequence is the accumulation of black pigments on the cartilage (***ochronosis***), particularly on the vertebrae, leading to a specific type of osteoarthritis known as **BAMBOO SPINE***
-->Other consequences:
1)Precipitates on heart valves & the kidney (leading to STONE FORMATION)
2)Can be excreted into the urine, & on exposrure to air it OXIDIZES & turns into a black color ("Black urine disease") when exposed to light & air

38

3 Major types of tyrosinemias

1)Tyrosinemia I (***most severe***)
2)Tyrosinemia III
3)Tyrosinemia II

39

Type I Tyrosinemia

-->Is the most SEVERE of all the tyrosinemias
-->Is caused by a deficiency of ***fumarylacetoacetate hydrolase***
-->Has a high prevalance in ***Quebec, Canada***
-->Consequences:
1)Causes the earlier steps in the tyrosine degredation
2)Growth retardation
3)Liver & Kidney failure (impairment of renal tubular absorption & liver failure)

40

Type II Tyrosinemia ("Oculocutaneous Tyrosinemia")("Richner-Hanhart Syndrome")

-->Is due to a deficiency in ***tyrosine aminotransferase***
-->Symptoms appear early in childhood, but the major differentiating points include:
1)***Photophobia***(abnormal sensitivity to light)
2)***Painful Skin lesions on the PALMS & SOLES***
3)Mental Retardation

41

Type III Tyrosiemia

-->The RAREST DISORDER OF THE THREE
-->Due to a deficiency in 4-hydroxyphenylpyruvate Oxidase, which converts 4-hydroxy-pheylpyruvate to ***homogentisic acid***
-->Clinical Symptoms:
1)Mild Mental Retardation
2)Seizures
3)"Intermittent Ataxia" (periodic loss of balance & coordination)

42

Metabolism of Tyrptophan

-->See notes for pathway

43

Features of Tyrptophan

-->Converted to imp. biom molecules in the body, such as:
1)Serotonin (neurotransmitter)
2)Melatonin (neurohormone)
3)Naicin (water solbule vitamin)

44

Hartnup Disease

-->Due to a deficiency of ***tyrptophan***
-->Can be induced by:
1) a high consumption of MAIZE (corn)
2)A ***low NAICIN*** deficiency
-->Consequences:
1)***Pellegra*** (4'Ds: Dementia , Diarrhea, Dermatitis, & Death)

45

Treatment of Tryptophan

-->Administration of **5-hydroxytryptophan (5-HTP) coupled to CARBIDOPA**
1)Carbidopa is a peripheral decarboxylase inhibitor which prevents the degredation of 5-HP to serotonin
2)Important b/c it is has been treated as a treament for ***Epilepsy*** and depression

46

Metabolism of Methoinine (see notes for pathway)

-->Methionine is converted to ***S-adenosylmethionine (SAM)***, which donates its methyl group to other compounds to form ***S-adenosylhomocysteine (SAH)***
-->Homocysteine can be broken down into ***succinyl CoA***, which enters into TCA cycle

47

Homocysteinuria

-->An autosomal recessive defect in ***Cystathionine Beta Synthase Deficiency***(due to a decreased affinity to PLP cofactor of Vitamin B6)
-->Major Signs & Symptoms
1)Sturctural defects (***pes carvs, genu valgum, pectus excavitum & carinatum -->High-arched feet, knock-knees, sunken chest-in & protrusion of the chest, respectively
2)**Lens subluxation***(downward & inward)
3)Intravascular thrombosis from arthersclerosis (leading to STROKE & MI)

48

Features of Metabolism of Amino Acids

-->All branched chain amino acids are converted to alpha keto acids by transamination
-->Alpha keto acids undergo oxidative decarboxylation and then subsequent catabolism
-->Valine form propionyl CoA which is converted to succinyl CoA which enters into TCA cycle (glucogenic)
-->Isoluecine forms both propionyl CoA and Acetyl CoA which may go for ketone bodies (both glucogeneic and keto genic)
-->Leucine forms acetoacetate (ketogenic)

49

Maple Syrup Urine Disease

-->An autosomal recessive defect in the **branched chain alpha keto acid dehydrogenase***
-->Leads to accumulation of leucine, isoleucine, & valine
-->Characterized by a ***sweet-smelling urine***, which smells like that of maple syrup
-->Consequences:
1)Infants seem healthy at BIRTH, but if left untreated, they suffer ***severe brain damage*** and eventually could die
-->Clinical Signs:
1)***Vomiting (due to incr. in α-ketoacids)
2)Opisthotnous (hyperextension and spasticity in which an individual's head, neck and spinal column enter into a complete "bridging" or "arching" position)
4)Mental Defects
5)DEATH if untreated

50

Metabolism of Glycine

-->See notes

51

Primary oxaluria

-->Is due to a defect in ***glycine transaminase*** (converts glyoxalate into glycine)
-->Causes the buildup of KIDNEY/BLADDER STONES, b/c they consist of calcium oxalate
-->Consequences:
1)The deposition of oxalate in the body, is knwon as ***oxalosis***