Biochem Trans - Protein Metab (LECTURE)

Biochemistry Protein and Amino Acid Metabolism
Dr. Santos Nov. 15, 2012
PROTEIN METAB 1
PROTEINS
With Nitrogen (CHON)
PROTEIN TURNOVER
o Continuous degradation and re-synthesis of cellular proteins
o Protein Turnover 1 2%
o Amino Acids reultilized for resynthesis 70 80%
o EXPLANATION:
o There is such a thing called PROTEIN TURNOVER, ito ay ang balance between the amount of
proteins undergoing breakdown and the amount of proteins undergoing synthesis. Ibig
sabihin araw araw may mga proteins na nacacatabolize at nasisynthesize.
o When proteins are degraded, they will be converted to amino acids tapos yung amino acids
ay maaaring ireutilize / recycle but 20-25% will be converted to urea.
UREA
o Final protein product of Protein catabolism in the body
o Excreted in the urine
o Proportional to Protein intake
o EXPLANATION:
o Urea is the final end product of protein catabolism in the body, sa urine lumalabas. the
amount of urea that you EXCRETE is equal to INTAKE.
PROTEIN HALF-LIFE
o Time required to reduce the protein concentration to 50% its initial value
o Can be 30 minutes to 150 hours
o Proteins with Short Half Life
Easily degraded
Protein Sequence (PEST Sequence):
P (Proline)
E (Glutamic Acid)
S (Serine)
T (Threonine)
o Proteins with Long Half Life
Most Rapidly Degraded
Aldolase
o Glycolysis Splitting Enzyme
Lactate Dehydrogenase
Cytochromes
o EXPLANATION:
o Half life - gaano kabilis madegrade yung protein. Time required to reduce its concentration
of protein to 50% of its initial value. The susceptibility of a protein to degradation.
o Yung mga proteins na may short half life ay usually yung (P,E,S,T) one letter abbreviations
to, eto sila = pro, glu, ser, thr. If you find this terapeptide in a protein ibig sabihin rapid
degradation.
LEMF and JEIF
o Long half life na protein ay aldolase (cleavage enzyme sa glycolysis), lactate dehydrogenase
(enzyme that converts pyruvate to lactate), cytochromes (members of ETC).
o Kapag mas importante yung function nung enzyme mas mabilis nadedegrade = ibig sabihin
yung mga rate limiting enzymes (phosphofructokinase 1, citrate synthase ) ay rapid ang
degradation / short half life.
o Those enzymes na constant lang ang function = mahahaba ang buhay.
RATE OF PROTEIN DEGRADATION
o More Important Enzymes are RAPIDLY degraded
Rate Limiting Enzyme
o Enzymes that are Constant are SLOWLY degraded (Long Half Life)
o Rate proportional to Nutritional intake
o EXPLANATION:
o The rate of protein degradation also depends upon nutritional status. pag kulang ng kinakain
= you are going to make up for your energy requirement by breaking down yung proteins,
kunwari naubos na yung fat reserve, tapos carb reserve mo....proteins na ang idedegrade
PATHWAYS THAT DEGRADED PROTEINS
LYSOSOMAL DEGRADATION
o Uses Lysosomes
o Proteins Degraded:
KFERQ Sequence:
K (Lysine)
F (Phenylalanine)
E (Glutamic Acid)
R (Arginine)
Q (Cysteine)
o EXPLANATION:
o Lysosomal degradation - remember na ang lysosomes ay may 50 hydrolytic enzymes.
o Degraded proteins are proteins that contains (KFERQ) pag nakita mo yung sequenze na to sa
isang protein, lysosomes can easily degrade it.lys, phe, glu , arg, gln
UBIQUITIN
o Proteins Degraded:
N Terminal
Asparatic Acid / Arginine rapidly degraded
Serine / Methionine NOT degraded
o EXPLANATION:
o Ubiquitin - pag ang N terminal (nasa umpisang amino acid ) ay aspartic or arginine, ag
degradation ng protein ay mabilis gamit ang ubiquitin. Pero pag ang N terminal ay
methionine or serine = no degradation.
SOURCES OF AMINO ACID
LEMF and JEIF

Exogenous Sources
o Diet
o Intake:
1 gram/ kg of ideal body weight
Body Weight
Tanhausers formula
Body weight computation with respect to Height (cm)
o EXPLANATION:
o Exogenous = diet, yung kinakain mo, when that undergoes digestion and absorption = you
get amino acids from it. so how much protein should you take everyday? = ( 1g/kg of ideal
body weight)
o Tannhauser's formula = computes for ideal body weight using height
o Convert your height to centimers 100
Endogeneous Sources
o Amino Acids synthesized by the Liver
o Break down of Body Tissues
o EXPLANATION:
o endogenous = amino acids that are synthesized by liver. also comes from proteins na
nabebreakdown. (diba nga pag nagbreakdown yung proteins, amino acids yung product)
AMINO ACID POOL

o Used:
Purine and Pyrimidine Synthesis
Glutamine
Aspartate
Glycine
Pophyrin Synthesis
Glycine
Creatine Synthessis
Glycine
Arginine
Methionine
Glutatthione
Glutamic acid
Cysteine
Glycine
o EXPLANATION:
o Amino acids are used to synthesized tissue proteins (eto yung most important function) and
essential non protein nitrogenous substances like purines (N1 ng purine - aspartic acid, N3 at
N9 - glutamine, carbon 4, 5, and 7 - glycine ,porphyrine requires glycine, creatine requires
(gly,arg,met), glutahione (glu,cys,gly).
PROTEIN DIGESTION and ABSORPTION
DIGESTION
LEMF and JEIF
o Mouth
No exnzyme
o Stomach
Pepsin
o EXPLANATION:
o Kapag ang amino acid na hindi nagamit, you catablolize it. you do not store.
o Enzymatic digestion ng proteins ay nagsisimula sa stomach. Complete digestion sa small
intestines.
ABSORPTION
o GAMMA-GLUTAMYL CYCLE
Also Meisters Cycle
Cycle
Gamma Glutamyl Transpeptidase (Protein)
o Allows the entry of Amino Acid
Amino Acid combines with GSH (reduced glutathione) at the N terminal side
o Glutathione = GLU CYS GLY
o AA GLU CYS - GLY
Peptide bond between Glutamic Acid and Cysteine Cut
o CYS GLY
o AA - GLU
Peptide Bond cut (AA GLU)
Glutathione regenerated, AA released
o Uses 3 ATP
o EXPLANATION:
o Absorption = Na dependent, active, or through facilitated diffusion, or the gamma glutamyl
cycle
o Gamma-glutamyl-cycle (meister's cycle)
This explains the absorption of majority of amino acids but not all
Like for example ang proline actually cannot be absorb in your meister's cycle
1st you must have the enzyme inside the cell membrane called GAMMA GLUTAMYL
TRANSPEPSIDASE (AKA membrane bound enzyme) --- iiiinternalized nya yung amino
acid siya yung magpapasok ng amino acid sa loob
Kapag nasa loob na iyong amino acid automatically makikipag combine xa sa (GSH)
reduced glutathione.
Ang formula ng glutathione ay like this, (ang glutamic acid ay nasa N terminal,-----
followed by cysteine, glycine ang nasa C terminal.)---- yung bagong pasok na amino
acid ay makikicombine sa glutamic (N terminal side)
At pag ang amino acid ay nakipag combine na sa glutamic acid= automatically the
peptide bond between glutamic and cysteine will be cut
So magkasama yung cysteine at saka yung glycine
Tapos magkasama naman yung glutamic at yung bagong pasok na amino acid
Ang next step ay you will cut the bond so that the amino acid now is free inside the
cell
Yung glutamic acid naman will again combine with cysteine at glycine to form back
glutahione. YOU HAVETO REGENERATE GLUTATHIONE. in the regeneration process,
you are going to need 3 moles of ATP.
LEMF and JEIF

For every amino acid that is absorb through the gamma glutamyl cycle you must
have: (the membrane bound enzyme, 1 mole of GSH and 3 moles of ATP)
LIVER in AMINO ACID METABOLISM
LIVER
o Site of ALL Amino acid Metabolism
Except:
Leucine
Isoleucine
Valine
(Metabolized in the brain and muscles)
o Process:
Protein Synthesis
Syntheis of Other Non Protein Compounds
Synthesis of Non-essential AA
Catabolism of unused AA
o EXPLANATION:
o The liver is the major organ for catabolism of amino acids EXCEPT branched chain amino
acids (val,leu,ile) kasi namemetabolize sila in the brain and muscles.
o Ang nangyayari sa liver ay 1st = protein synthesis, 2nd = you also synthesize nitrogen
containing compounds (purines, pyrimidines etc.) .
CLASSIFICATION OF AMINO ACIDS
ESSENTIAL AMINO ACIDS

o Also Indispensible
o Cannot be synthesized in the body
o Provided in the diet
o Essential Amino Acids
Trp
Val
Thr
Met
Arg
Actually Not Essential (SEMI-ESSENTIAL)
Provided in the diet, also synthesized in the body
Presence of Pathway that can synthesize Arg
However, insufficient amount of Arg produced
Phe
His
Ile
Leu
Lys
o Complete Protein
Contains the Essential Amino Acids
Examples:
Milk
Meat
LEMF and JEIF

Eggs
o EXPLANATION:
o Essential amino acids (indispensable) - amino acid na hindi kayang gawin ng katawan mo
kaya kailangan mo sa diet (trp,val,thr,met,arg,phe,his,ile,leu,lys) pag present lahat etong
mga to ang tawag sa protein ay complete protein(it can sustain life by itself)
o Example = milk,meat, eggs
NON ESSENTIAL AMINO ACIDS

o Dispensable Amino acids
o Can be synthesized by the body
o Incomplete Protein
Does not contain one of the Essential AA
Limiting AA
Essential AA that is lacking in a protein
Examples
Zein
o Found in corn
o Lacks Tryptophan
o EXPLANATION:
o Non essential amino acids (dispensable) - kayang isynthesize ng body mo. xempre yung mga
hindi kasama sa essential amino acids, ibig sabihin dito sila nabibilang pero you will
eventually realize that arginine is not essential kasi may pathway sa body na
magsisynthesize ng arginine. kaya siya kasama sa essential kasi kulang ang kayang
isynthesize ng body.(kaya ang arginine ay semi essential)
o If one or more of the essential protein is lacking = incomplete protein xa.
o Example protein found in corn (zein) trp yung kulang. ang general term dun sa kulang na
amino acid ay limiting amino acid.
ENZYMES USED IN AMINO ACID BIOSYNTHESIS

o Glutamate Dehydrogenase
For Glutamate (Glu)
o Glutamine Synthetase
For Glutamine (Gln)
o Amino transferases / Transaminases
Used for multiple Amino Acids
For other AA
AMINO ACID CATABOLISM
Removal of the alpha-NH2 group
o EXPLANATION:
o Removal of the alpha-NH2 group - yung NH2 ay magiging ammonia at yung matitira ay
magiging keto acid. reversible to. just combine again ammonia to keto acid = amino acid ulit
yun
o Products: Ammonia + Keto Acid
LEMF and JEIF

o 3 WAYS OF THE REMOVAL of the ALPHA-NH2 GROUP

1) OXIDATIVE DEAMINATION
Removal of Amino Group
o Produces a Keto Acid
o Amino Acid Keto Acid + NH3
o *Reversible
3 Enzymes used:
o Glutamate dehydrogenase
MOST ACTIVE ENZYME
Glutamate Alpha Ketoglutarate
EXPLANATION:
Glutamate dehydrogenase - converts glutamic acid to alpha
keto glutarate subalit yung keto acid na makukuha mo pag
glutamic acid is called alpha keto glutarate (sinabi nya na yun
ah). pwede mo tong mareverse to combine again the amino
group and alpha keto glutarate = glutamic acid (using the same
enzyme) MOST ACTIVE enzyme for oxidative deamination
o L-Amino Acid Oxidase

Aspartic Acid Oxaloacetate + NH3
Alanine Pyruvate + NH3
*Reversible
EXPLANATION:
Pag aspartic acid ---- Oxaloacetate + NH3 (keto acid to)
Pag alanine ---- Pyruvate + NH3 (keto acid to)
Bawat amino acid = may kanya kanyang keto acid yan.
Example
o Gly ----- ang keto acid ay glyoxylic acid
o His ----- urocanic acid
Three most important keto acids in your body:
Oxaloacetate
Pyruvate
alpha keto glutarate
o D-Amino Acid Oxidase

Not found in Human
All AA in Human are in L Configuration
EXPLANATION:
D- amino acid oxidase -we do not have this kasi the amino acids
na nasa katawan natin ay pag aaari ni L-Type. dalawa lang yung
D amino acids natin = D-aspartate at D-serine. so hindi
nagfafunction to sa ating body.
Zellweger Cerebrohepatorenal Syndrome (CHRS)

o Deficiency of L-Amino Acid Oxidase
o Manifestations:
LEMF and JEIF
Brain
Liver
Kidneys
2) NON-OXIDATIVE DEAMINATION
Amino Acid Keto Acid + NH3
Enzymes:
o Amino Acid Dehydrases
Hydroxy AA
Serine
Threonine
Tyrosine
o Amino Acid Desulfhydrases
Sulfur-containing AA
Cysteine
Homocysteine
Methionine
EXPLANATION:
Non - oxidative deamination- pareho lang sa oxidative. You remove the
amino group, you get the ammonia plus the keto acid. Gagamit ka ng ibang
enzyme. (remember, magrerelease ka ng free ammonia)
Enzymes involved:
o Amino acid dehydrase
this will act on the hydroxyl containing amino acids (ser, the,
tyr) at ang coenzyme nito ay pyridoxal PO4.
o Amino acid desulfhydrase
Act on sulfur containing amino acids (cys, homocysteine, met)
3) TRANSAMINATION
Enzymes:
o Transaminases
o Aminotransferase
o Synthesis of new other AA
Amino Group of AA, transferred to a Keto Acid
o Keto Acid doesnt have an Amino Group
Amino Acid A+ Keto Acid A Keto Acid B + Amino Acid B
Pyridoxal Phosphate
o Vitamin B6 Phosphate
o Carrier of AA group during Transamination
o Coenzyme for Transamination
FAVORABLE
o Ammonia doesnt accumulate
AA that DOESNT go Transamination
o Lysine
o Threonine
o Proline
EXPLANATION:
LEMF and JEIF

Transamination - itatransfer ang amino group to a keto acid. kasi yung keto
acid wala xang amino group kaya madali xang tumanggap. pag amino acid ay
tinangallan ng amino group magiging keto acid siya.
Enzymes involved:
o Transminases - can be use to synthesize new amino acids
o Reactants
AMINO ACID+KETO ACID = new keto acid and new amino acid
Example:
Amino acid: Alanine ---- keto acid: alpha keto glutarate
Ang keto acid na makukuha mo sa alanine ay pyruvate.
ang alpha keto glutarate naman, once na maaccept nya
yung amino group ay magiging glutamic acid.
Everytime you do transamination, you can form a new amino acid, depending
upon the ketoacid that accepts the amino group. halimbawa, yung keto acid
mo na taga accept ng amino group ay oxalo acetate = your new amino acid
now will be aspartic acid.
The carrier / coenzyme for trans amination = PYRIDOXAL PHOSPATE (vitamin
b6 phosphate)
Sa trans amination = wala kang ammonia na product kasi yung tinanggal mo
na amino group is incorporated into the keto acid therefore no release of free
ammonia. mas gusto ng body yung kasi ammonia is toxic if it accumulates.
(lys,thr,pro = THEY DO NOT UNDERGO TRANSAMINATION)
Decarboxylation
o Removal of Carboxyl group
o Released as CO2
o Formation of Biogenic Amines
AA CO2 + Amine
o Example:
Histidine Histamine
Serotonin Trp
Catecholamine Tyr, Phenlyalanine
Oxygenation
o Addition of O2
o Phe + O2 = Tyr
One Carbon Transfer

o Removal of R-group
WAYS OF DETOXIFYING AMMONIA
Reversal of Glutamate Dehydrogenase Reaction

o NH3 + Alpha keto glutarate Glutamic Acid
Glutamine Formation
o Glutamic Acid + NH3 Glutamine
Enzyme: Glutamine Synthetase
Formed in the Brain
LEMF and JEIF
o Glutamine goes to the kidneys Glutamic Acid + NH3

Enzyme: Glutaminase
NH3 goes to Urine
Glutamine
MAJOR SOURCE of NH3 in the URINE
o EXPLANATION:
o Glutamine formation = major way of detoxifying ammonia sa brain. It reacts the glutamic
acid with ammonia through the enzyme glutamine synthetase so that now YOU FORM =
GLUTAMINE!
o Etong glutamine na to ay pupunta sa kidneys .
o Pag nasa kidney na, yung glutamine will be converted back to glutamic acid plus ammonia.
o The enzyme for this is glutaminase (hindi mo pwedeng gamitin yung same enzyme).
o At yung ammonia ay maeexcrete sa urine. ( kaya pag tinanong ka ...what is the major source
of ammonia excreted in the urine = GLUTAMINE )
Asparagine Formation
o Aspartic Acid + NH3 Asparagine
Urea Formation
o MOST MAJOR WAY OF DETOXFYING AMMONIA
o Urea formation is the major means by which the liver detoxifies ammonia.
o Ayun nga, sa liver ang urea formation. among all the ways by which your body detoxifies
ammonia, yung urea formation ay ang MOST MAJOR way to detoxify it.
o Kasi sa liver ang majority ng catabolism ng amino acids so doon nafoform yung maraming
ammonia
o UREA CYCLE (Krebs Heseleit Cycle)

Location: Liver
Specific Location: Cytosol and Mitochondria
STEPS:
Step 1
o ATP + CO2 + NH3 + H20 Carbamoyl Phosphate
Enzyme: Carbamoyl PO4 Synthetase I
Deficiency: Hyperamonemia Type 1
RATE LIMITNG
Step 2
o Carbamoyl PO4 + Ornithine Citrulline
Enzyme: Ornithine Transcarbamoylase
Deficiency: Hyperamonemia Type 1
MOST RATE LIMITING
Presence of Ornithine
Ornithine requires a transporter
Step 3
o Citrulline goes out the mitochondria Arginosuccinate
Enzyme: Arginosuccinate Synthetase
Deficiency: Citrullinemia
Step 4
o Arginosuccinate Arginine
LEMF and JEIF
Enzyme: Arginosuccinase
Deficiency: Arginosuccinate Aciduria
Releases Fumarate
Goes into Krebs Cycle (Krebs Bi-cycle)
Step 5
o Arginine Ornithine
Enzyme: Arginase
Deficiency: Argenemia
RATE LIMITING
Urea released
Step 6
o Ornithine goes into the Mitochondria
Via Ornithine Transporter
Triple H Syndrome
Ornithine Transporte Gene Mutation
No Ornithine Transporter
o Ornithine doesnt go inside mitochondria
o Urea Cycle Stops
o NH3 Accumulates
Triple H
o Hyperornithenemia
Accumulation of Ornithine in the Cytosol
Ornithine doesnt go inside the
mitochondria
No Ornithine Transporter
o Hyperammonemia
Ammonia Intoxication
Accumulation of Ammonia in the blood
Ornithine doesnt go inside the
mitochondria
Urea cycle stopes
Ammonia accumulates
o Homocitrullinea
Citrulline comes out of the urine
ATPs
NO ATP PRODUCED
ATP USED
o 1sd step 2 ATP
o 3rd Step 1 ATP
ATP converted to AMP + PPi
PPi converted to inorganic phosphate
Uses 1 ATP
o TOTAL ATP USED: 4 ATP
EXPLANATION:
CYCLE
Pathway that involves both cytosol and mitochondria.
Ang unang reaction ay inside the mitochondria bubuo ng CARBAMOYL PO4 =
ATP, ammonia, CO2 and water reacts to form carbamoyl PO4 at ang enzyme
ay CARBAMOYL PO4 SYNTHETASE 1 (CPS1).
2nd step carbamoyl phosphate reacts with ornithine to form citruline at ang
enzyme para dun ay ornithine transcarbamoylase -----citruline gets out of the
LEMF and JEIF
cytosol it will now react with one more ammonia in the form of aspartic acid.
Yung pangalawang ammonia na papasok is in the form of aspartic acid and
the enzyme for that is argininosuccinate synthetase. (sabi nya 4th reaction,
pero diba 3rd palang) argininosuccinate is cleave to form fumarate and
arginine. eto daw yung sinasabi nya na you can synthesize arginine in the
body, pero as you can see, this arginine ay hindi magagamit for protein
synthesis kasi it will immediately undergo breakdown to urea and ornithine.
so kung kailangan mo ng arginine para sa protein synthesis, kailangan
manggaling siya sa diet mo.
Urea now gets out with the urine----ornithine is recycle---papasok ulit siya sa
mitochondria.
CPS 1 vs. CPS 2 (Carbamoyl Phosphate Synthetase)

CPS1
o sa mitochondria
o requires an activator (ang pangalan nung activator ay N-AGA (N acetyl
glutamic acid)
CPS2
o sa cytosol
o does not require an activator
ENZYMES IN THE UREA CYCLE:

Carbamoyl PO4 synthetase I
Ornithine transcarbamoylase
Argininosuccinate synthetase
Argininosuccinase
Arginase
RATE LIMITNG STEPS

Step 1 = CPS
Step 2 = Ornithine transcarbamoylase
Step 5 = Arginase
Karamihan ng pathways na naaral na natin, isa lang ang rate limiting step
pero dito sa urea cycle tatlo. pero kung tatanungin daw.... kung isa lang ang
rate limiting step sa urea cycle, ano ito? = THE MOST RATE LIMITING AMONG
THE THREE ENZYMES AY ---- ORNITHINE TRANSCARBAMOYLASE.
Eto yung kailangn mo to convert carbamyl phosphate to citruline.
Ang isa pang dahilan ay kasi daw, if you look at the reaction, saan nanggaling
yung ornithine? edi sa cytosol! papasok siya sa pangalawang step na. hindi
naman siya pumasok sa 1st step, malamang! and the ornithine requires
transporter para makapasok sa loob ng mitochondria.
Pag kailangan mo ng transporter---there must be a gene for that kasi protein
yung transporter. Now there could be a situation wherein there will be
abnormalities sa ornithine transporter gene... pwedeng magkaroon ng
mutation---pag nangyari yun, wala ka ngayong gene na papasok sa
mitochondria---- urea cycle will stop after the 1st step... so yun ang kwento ni
lola basyang! (BOOM KA DUDUNG!)
ATP
Walang napoproduce na ATP sa urea cycle. GUMAGAMIT KA LANG --- 2 ATPs sa
first step, if you look at the third step, you need 1 ATP to convert cituline to
argininosuccinate BUT in the hydrolysis of this ATP will produce AMP + PPi,
usually when ATP undergoes hydrolysis---ang product usually ay dapat
LEMF and JEIF

ADP+Pi------- pero sa urea cycle nga ang ATP ay nagiging AMP + PPi. etong PPi
na to should undergo conversion to two inorganic phosphates and that will
require another ATP.
So all in all 4 ang kailangan na ATPs for entire urea cycle. sa 4th reaction, you
release fumarate.... saan ba pwedeng pumasok ang fumarate? = sa krebs
kasi part siya ng krebs diba? so this fumarate can enter the krebs cycle ----
you will now have the krebs cycle side by side with urea cycle at ang tawag
doon ay krebs BICYCLE. hahahaha,, alam ko natatawa ka =) ---- ang linkage
nung dalawang cycle ay fumarate.
o UREA
Secreted in the Urine
Diuretic
High protein Diet:
High excretion of Urea
High Specific Gravity of Urine
High Solid Content of Urine
High Volume of Urine
EXPLANATION:
Ang urea ay diuretic ---- iniincrease nya yung volume ng urine. --- so kung ikaw ay
mag hahigh protein diet = increase urea excretion in the urine------. dahil ang urea ay
solid it will increase the specific gravity of the urine.
CLINICAL CORRELATION (yes may clinical correlation na sa biochem)
CONGENITAL ANOMALIES in the UREA CYCLE

o Involves the enzymes of the Urea Cyle
Hyper ammonemia type 1
pag yung 1st enzyme ang deficient
Hyper ammonemia type 2
pag yung 2nd enzyme ang deficient
Citrolinemia
pag yung 3rd enzyme ang deficient
Argininosuccinate aciduria
pag yung pang 4 ang deficient
Argenimea
pag yung pang 5 enzyme ang deficient
o Kahit isa sa enzyme sa urea cycle ang mawawala titigil ang urea cycle = accumulation of
ammonia.= inborn errors of urea cycle
o Lahat tong inborn error na to will lead to hyper ammonemia = ammonia intoxication
AMMONIA INTOXICATION in LIVER DISEASE

o Severe Liver Disease Urea Cycle Stops Liver Disease NH3 goes to Brain NH3
combines with Glutamic Acid (in the Brain Glutamine Glutamine goes to Kidneys
Glutamine Glutamate + NH3 NH3 secreted in the urine
o Depletion of Glutamic Acid in the Braine
Brain will produce its own Glutamic Acid
Alpha Keto Glutarate Glutamic Acid
Use Alpha Keto Glutarate (from Krebs Cycle)
Alpha Keto glutarate will be depleted
LEMF and JEIF
Krebs cycle will NOT produce ATP

No ATP, Brain goes into Coma
o EXPLANATION:
o Severe liver disease = urea cycle stops = ammonia will accumulate in the liver = spill out sa
systemic circulation tapos pupunta sa brain kasi yun yung most sensitive = pag nagpunta sa
brain, itatry nya itong icompensate / idetoxify by converting it to glutamine yung glutamine
ay pupunta na sa kidneys at yung reaction ay marereverse .. babalik siya sa pagiging
glutamic acid plus ammonia at yung ammonia ay makakalabas sa urine.
o However, if the amount of ammonia ay sobrang dami, there will come a time na mauubos
yung glutamic acid. ang gagawin ng brain ay magtatry mag produce ng glutamic acid na
ang source ay alpha keto glutarate ----- you can easily convert alpha keto glutarate to
glutamic acid using the enzyme glutamate dehydrogenase----- (diba nga glutamate
dehydrogenase ang MOST ACTIVE ENZYME for oxidative deamination ) which makes
glutamic acid your most active amino acid.
o Ang glutamate dehydrogenase ay makikita mo halos sa buong parte ng katawan mo ---kaya
pag nakakita nito, pwede agad tong maconvert sa glutamic acid however ulit---- saan
mangagaling yung alpha keto glutarate? ------ sa krebs diba? so yung krebs cycle will be
channeled to glutamic acid formation. titigil na ang krebs = no ATP formation = COMA
THERAPHY for UREA CYCLE DEFICIENCY

Limit Protein Intake and Build Up of Ammonia
o Limit ingestion of AA
o Give Levulose / Lactulose
Promotes excretion of ammonia in the feces
o Give antibiotics
Kill NH3 producing bacteria
Remove Excess Ammonia
o Compounds that bind covalently AA and produces substance released in the urine
o Compounds:
Benzoate + Glycine = Hippuric Acid
Phenyacetate + Glutamine = Phenyacetlygln
Replace any intermediate missing from the cycle
o COMA
Give glutamic Acid
Alpha Keto glutarate will not be depleted
PROTEIN METAB 2
METABOLIC FATES OF KETO ACIDS
Synthetic Pathway
o Alpha keto acid + NH3 alpha AA
LEMF and JEIF
Glucogenic pathway
o Gluconeogenesis
Ketogenic Acid
o Purely ketogenic AA:
Lysine
Leucine
Cannot be converted to glucose ONLY
o Both glycogenic and ketogenic
Ile
Phe
Tyr
Trp
EXPLANATION:
Diba dalawa yung product ng metabolism ng amino acids ----- yung amino group at keto acids
Yung keto acid ay pwedeng maconvert back to amino acid. I-combine mo lang ulit yung keto acid
at ammonia --- magiging amino acid na ulit yun
Ang isa pang way ng keto acid ay pwede siyang pumasok sa gluconeogeneseis. diba nga, pwedeng
maging glucose ang amino acids by entering kreb's cycle tapos reverse glycolysis.
May mga amino acids na pwedeng pwedeng maging ketone bodies.
Dati daw, may isa lang na purely ketogenic amino acid pag sinabing purely ketogenic it cannot be
converted to glucose.
Pwede rin siyang maging ketone bodies but as of the 27th edition of harper's sinama narin yung
LYSINE as PURELY KETOGENIC. so ngayon may dalawa ka ng pure ketogenic amino acids LYSINE
and LEUCINE
For the other amino acids there are four na both glycogenic and ketogenic. ibig sabihin, you can
convert them to glucose and ketone bodies at the same time. Etong apat na both glycogenic and
ketogenic ay (ile, phe, tyr, trp)
The rest nung amino acids, purely glycogenic na.
CATABOLIC DISPOSITION OF CARBON CHAINS OF AMINO ACIDS
Amino Acids can:

o Go into the Krebs Cycle
o Converted to Pyruvate
Eventually to Glucose via Gluconeogenesis
EXPLANATION:
This is how your amino acid can enter you kreb's cycle kung gusto mong maconvert yung amino
acids sa glucose, kailangan muna nilang maconvert sa pyruvate.
Tapos yung pyruvate ay macoconvert to acetyl coA papuntang kreb's cycle. ( ala, cys, gly, ser, thr )
etong 5 na to ang maaring iconvert to pyruvate
Meron din limang amino acids that enters through ALPHA KETO GLUTARATE. ( glu, arg, gln, his, pro)
if you want to convert these amino acids to glucose, dapat iconvert muna sila sa alpha keto
glutarate
Succinyl coA naman yung entry point para sa ( ile, met, val )
Yung ( phe, tyr, ) fumaric acid yata to... hindi ako sure sa part na to sobrang bilis ng mga
pangyayari.
METABOLIC PATHAWAY of PHENYLALANINE and TYROSINE

LEMF and JEIF
ENZYME
o Phenylalanine monooxygenase
o Phenylalanine hydroxylase
SUBSTANCE DERIVED FROM PHE and TYR:

o Epinephrine and norepinephrine
o Melanin
Pigment responsible for complexion
o T3 and T4 thyroid hormones
o EXPLANATION:
o They always go together. They have the same catabolic pathway.
o Dahil you can easily convert phe to tyr by oxygenation. so tandaan mo na ang process na
nagcoconvert sa phe to tyr ay oxygenation.
INBORN ERROR
o PHENYLKETONURIA (PKU)
ENZYME:
Phenylalanine hydroxylase
CO-ENZYME:
NADPH
DIHYDROBIOPTERIN
CAUSES:
Deficiency / absence of Enzyme
Deficiency / absence of Coenzyme
No reducing enzyme DHB reductase
o DHB reductase Converts DHB to THP
EXPLANATION:
Kung titingnan mo yung detailed conversion ng phe to tyr. you need the major
enzyme PHENYLALANINE HYDROXYLASE sometimes tinatawag din ito na
PHENYLALANINE MONOOXYGENASE
Tapos kailangan mo pa ng dalawang coenzymes. yung dalawa na kailangan mo ay
NADPH na pwedeng makuha sa HMP shunt at DIHYDROBIOPTERIN ( hindi ako sure sa
spelling )
3 causes of PKU:
deficiency of major enzyme phe hydroxylase
wala kang biopterin or NADPH or BOTH ( no coenzyme )
you dont have enzyme that will reduce the dihyrobiopterin to
tetrahydrobiopterin. yung enzyme na gumagawa nung pagrereduce ay
dihydrobiopterin reductase.
Pag ang phe ay hindi maconvert sa tyr ----- phe will follow a minor pathway which is
conversion of phenylpyruvic, phenyllactic and phenylacetic acid.
Mag aaccumulate ngayon yung phe plus the three ketoacids.
If phe accmulates in your brain magkakaroon ka ng mental retardation so yun yung
isang major manifestation of PKU.
pag accumulation ng phe sa urine yung 3 keto acids na to pag lumabas sa urine will
going to cause the mousey odor of urine.
LEMF and JEIF
Also bec you cannot convert phe to tyr there will be no formation of melanin, edi
magkakaroon ng HYPO PIGMENTATION sa PKU.
o ALCAPTUNIRIA
Deficiency in Monogentisate Dehydrogenase
Triad of Alcaptunuria
Black Urine
Arthritis
Ochronosis
EXPLANATION:
Ang isa pang inborn error ng phe at tyr ay ALKAPTONURIA
Dito sa alkaptonuria, you dont have the enzyme that converts homogentinsic acid to
maleylacetoacetate. at yung enzyme na wala ay HOMOGENTISATE 1,2 DIOXYGENASE
So mag aaccumulate yung homogentinsic acid at mag accumulate yun sa connective
tissues mo causing ochronosis. ang ochronosis ay ang pigmentation of connective
tissues.
And this can easily lead to arthritis,tapos pag lumabas yung homogentinsic acid sa
urine ang magiging kulay ng ihi mo ay black.
Black kasi yung kulay ng homogentinsic acid. eto yung tinatawag na TRIAD OF
ALKAPTONURIA. ( ochronosis, arthritis, black urine )
o ALBINISM
White skin
No protection against UV rays, easily develop skin cancer
EXPLANATION:
Another inborn error, you don't have the enzyme that convert dopamine to melanin
Yung enzyme na yun ay TYROSINASE
Kung wala kang melanin formation, magkakaroon ka ng ALBINISM you don't have
melanin ibig sabihin wala kang protection sa UV rays ng sun kaya you can easily
develop skin cancer
o TYROSINEMIA
Type II
Occulo Cutaneous Tyrosinemia
Richner ?? Syndrome
No Amino Transferase
Occulo Cutaneous Manifestation
o Manifesations in the eyes and skin
Type I
Hepatorenal Tyrosinemia
No Fumaryl acetoacetate hydrolase
o Accumulation of fumaryl aceto acetate and maleylacetate
o DNA timorigenesis
EXPLANATION:
Another inborn error ay TYROSINEMIA . dalawang klase yung tyrosinemia,
LEMF and JEIF
Yung una (type 1 - hepato renal tyrosinemia) wala kang enzyme na nagcoconvert ng
tyrosine to phenylpyruvate.
Yung type 2 ay tinatawag din na RICHNER-HANHART SYNDROME at ito ay manifested
by occulocutaneous manifestations kaya ang isa pang tawag dito ay occulocutaneous
tyrosinemia. occulo means eyes so you have manifestation sa mata at sa skin kasi
nga cutaneous.
Ulit lang. sa type 1 wala ka nung enzyme that converts fumaryl acetoaetate to
acetoacetate.
Yung enzyme na dapat gagawa nun ay fumaryl acetoacetate hydrolase.
Kaya magkakaroon ng accumulation of fumaryl acetoacetate and malylacetate
these 2 substances can cause tumor formation
Among the two tyrosinemias, mas serious type yung type 1.
Pwede kang magkaroon ng liver failure at renal failure
May rickets ka sa type 1. ang rickets ay deficient ang vitamin D in children
Ito ay dahil sa diseased yung kidney so ibig sabihin you cannot form the most active
form of vitamin D. yung most active form of vitamin D which is 125
dihydroxycholecalciferol ay sinisynthesize sa kidneys.
TRYTOPHAN
Also KYNURERINE ANTHRANILATE PATHWAY

o Tryptophan Niacin
COENZYMES:
o Vitamin B2
o Vitamin B6
PELAGRA
o Niacin Deficieny
o Vitamin B2 and B6 deficiency causes pelagaera
NO Niacin formation
Vit B6 deficiency
o Xanthurenate formation
o Elevation of xanturenate
o Trytophan load test
Detect Vit B6 deficiency
Trytophan given to check if it will be converted to niacin
EXPLANATION:
Most important substance that you can derive from trp is niacin ( vitamin B3 ).
You call the pathway for the conversion of trp to niacin KYNURERINE ANTHRANILATE pathway.
o That is conversion of 60 mg of trp to 1 mg of niacin.
o In the conversion, you need to have 2 coenzymes
o Yung dalawang coenzymes ay vit. B2 and B6 ----- pag deficient ang B2 at B6 there will be no
niacin formation ang mangyayari ay magkakaroon ka ng pellagra ( niacin deficiency ) like
manifestations
o For B6 kung ang vitamin B6 ang deficient hydroykynurenine is instead channel towards
different pathway
o So hindi macoconvert yung hydroxykynurerine to niacin.
Trp load test

o Diagnosing vit. b6 deficiency.
LEMF and JEIF

o You give trp and then you measure the level of santorenic acid sa urine
o hindi ako sure sa santorenic, wala rin akong makita sa net pero yun ang narirnig ko
pag mataas daw, may deficiency ka ng B6
CONVERSION OF TRYPTOPHAN
o CONVERSION TO ALANINE
Tryptophan Alanine
EXPLANATION:
In the catabolism of trp it leads to formation of alanine
Karamihan ng non essential amino acids that you can synthesize are actually
synthesized from the essential
Diba nga, tyr is not essential so you can get it from phe which is essential. ngayon
naman, trp can give you ala.
o CONVERSION TO SEROTONIN
Tryptophan Serotonin
Trytophan converted to serotonin
CARCINOID SYNDROME
Overproduction of Serotonin
Diagnosis:
o Amount of 5-hydroxyindoleacetate in the urine is high
EXPLANATION:
Another important substance derived from trp is serotonin
This is derived from decarboxylation.
Eto yung amine na makukuha mo sa trp.
Ito ay neurotransmitter, vasoconstrictor and stimulates muscle contraction
This is excreted through the urine as 5-HYDROXYINDOLEACETIC ACID (5-HIAA)
Carcenoid syndrome
overproduction of serotonin
you can diagnose it by measuring the amount of 5-HIAA in the urine. pag may
carcenoid syndrome, there will be elevation of 5-HIAA sa urine.
o MELATONIN FORMATION
Melatonin
EXPLANATION:
Another important substance derived from trp is melatonin. ito ay ginagamit to
induce sleep.
INBORN ERRORS:
o HARTNUP DISEASE
Cannot convert Tryptophan to Niacin
LEMF and JEIF
Niacin Deficiency
3 Ds of Pelagra
Diarrhea
Dementia
Dermititis
Cassals necklace
Lesions in the neck
Gloves ad Stocking
Lesions In the legs and arm
EXPLANATION:
Hartnup disease
You cannot convert trp to niacin that's why you are going to show manifestations of
pellagra
Ang 3 d's ng pellagra ay diarrehea, dementia and dermatitis
Lesions of the skin are found in the areas around the neck,arms and legs
Yung mg lesions sa neck ay tinatawag na CASAL'S NECKLACE
At yung lesions sa arms and legs ay tinatawag na GLOVES and STOCKINGS LESION
Another important substance derived from trp is serotonin. this is derived from
decarboxylation.... eto yung amine na makukuha mo sa trp. ito ay neurotransmitter,
vasoconstrictor and stimulates muscle contraction. this is excreted through the urine
as 5-HYDROXYINDOLEACETIC ACID (5-HIAA)
o BLUE DIAPER SYNDROME

Tryptophan not absorbed in the small intestine
Goes to large intestine
Converted to indole asnd skatole
Bad odor of stool
Indole converted to indican
Blue urine comes our Blue diaper syndrome
Familial disorder
Hypercalcineamia
Nephrocalcinosis
EXPLANATION:
blue diaper syndrome
Hindi maabsorb yung trp sa small intestines so it will now go to the large intestines
and it will be converted to indole and skatole. ang indole and skatole are two
substances responsible for unpleasant odor of stool.
Yung indole is absorb sa large intestines tapos pupunta sa liver tapos macoconvert to
indicant
Tapos lalabas yung indican sa urine. yung indican ay kulay blue so kung lalabas yung
indican sa urine ito ay blue.
kaya siya tinawag na blue diaper syndrome (check internet source sa youtube: LA
BLUE GIRL ) may hypercalcemia din pag may high levels of calcium ka prone to
develop stones in the kidney.
HISTIDINE
LEMF and JEIF
Histidine urocanic Acid Glutamic Acid alpha keto glutarate

FIGLU
o N-formiminoglutamate
o Deficiency in B9 (Folic Acid)
FIGLU not converted to Glutamic Acid
Figlu goes out in the urine
o FIGLU excretion test
Histidine Load test
FIGLU not converted to Glutamic Acid because of Folic Acid deficiency
EXPLANATION:
In the catabolism of His, you are going to remove the amino group and you get urocanic acid.
so yung urocanic acid is the keto acid derived from his.
normally yung urocanic acid ay part ng sweat glands. this can go to formation of GLU.
Remember, sinabi nya daw nung simula that his can be converted to GLU and then to alpha keto
glutarate.
pero bago mangyari yung yung conversion of his to glu,,,
dapat it should pass through the formation of FORMIMINOGLUTAMIC ACID ( FIGLU ) figlu can
only be converted to glu if you have adequate amounts of TETRAHYDROFOLIC ACID ( vitamin B9
).
if you lack folic acid, FIGLU will not be converted to glu instead ito ay lalabas sa urine.
kaya may tinatawag tayong FIGLU excretion test (histidine load test ) bigyan ng HIS ang
pasyente tapos measure the amount of FIGLU sa urine.
pag tumaas yung amount ng FIGLU sa urine that means there is deficiency of folic acid.
INBORN ERROR
o HISTIDENEMIA
Deficiency in Histidase
Histidine not converted to Urocanic Acid
Diagnosis: Skin Biopsy
EXPLANATION:
Sa histidine may isa lang na inborn error (HISTIDINEMIA) - deficiency of
HISTIDASE.
there will be no conversion of his to urocanic acid.
you can show that through skin biopsy
the skin biopsy shows abscence of urocanic acid in the sweat ( eto yung way ng
pagdadiagnose ng histidinemia )
this is manifested by convulsive seizures,
kung may baby ka na nag coconvulsive seizure kahit walang fever.. possible ito .
VALINE, LEUCINE, ISOLEUCINE
Not metabolized in the liver, brain and muscle

o Step 1
Transamination
Valine Keto Acid: a- ketovaleric acid
Leucine Keto acid: a- isocaproic acid
LEMF and JEIF
Isoleucine keto acid: a-

o Step 2
Decarboxylation
Removal of CO2
Keto Acid converted to COA (co-enzyme A) form
o EXPLANATION:
o Not metabolize sa liver
o Sa brain and muscles sila nacacatabolize. basta branch chain amino acids ( val, leu, ile )
pare pareho ng 1st step
o ang unang step sa kanilang catabolism ay transamination
o after nun ... kukununin yung keto acids..for valine, ang keto acid ay alpha keto isovaleri acid,
o for leu, ang keto acid ay alpha keto iso caproic acid,
o for ile, you call the keto acid alpha keto beta metyl valeric acid
o ang 2nd step sa catabolIsm ng branch chain amino acids ay decarboxylation.... tatanggalan
mo ng CO2. the keto acid now is converted to COA form.
INBORN ERROR
o Deficiency of enzymes:
Alpha keto acid dehydrogenases
Alpha ketoisocaproic acid not converted to isovaleryl CoA
Leucine: alpha ketoisocaproic dehydrogenase
Valine:
Isoleucine:
o Maple Syrup Urine Disease (MSUD)
Branch chain ketonuria
Accumulation of Amino Acids in the brain
AA not converted
Toxicity in the brain
Keto Acid secreted in the urine
Maple syrup odor of the urine

o Isovaleric acidemia
Deficiency of Isovaleryl dehydrogenase
Accumulation of isovaleric acid
Cheesy odor of breath
o EXPLANATION:
o there is one inborn error associated with the three branch chain amino acids.
o there is a deficiency of the enzyme that converts the keto acid to coA.
wala sila nung enzyme na magcoconvert ng isocaproic to isovaleryl, alpha keto
isovaleric , alpha keto metyl valeric. you call the enzyme individually.
pag isa isa, pag valine you call the enzyme alpha keto isovaleric dehydrogenase.
pag leu, yung enzyme ay alpha keto isocaproic dehydrogenase,
pag ile, yung enzyme ay alpha keto beta metyl valeric dehydrogenase
But you can call them as one, ALPHA KETO ACID DEHYDROGENASE.
(sometimes called alpha keto acid decarboxylase )
AT ETO YUNG ENZYME NA DEFICIENT SA maple syrup urine disease (branchchain
ketonuria)
you cannot convert the keto acids of branch chain amino acids to the coA form.
mag aaccumulate ngayon yung 3 keto acids together with the amino acids.
LEMF and JEIF
pag nag accumulate yung 3 branch chain sa brain is toxic. lalabas yung keto acids sa
urine ---- yun yung maple syrup na odor
o tong PKU at MSUD ay kasama sa new born screening.

o kasi pag nadiagnose mo g maaga, pwede mong mapigilan yung onset ng mental retardation.
o you prevent accumulation nung amino acids. give milk preparations na wala nung amino
acid na saki. ( milk prep without phe, milk prep without branch chain amino acids
o one important substance that you can derive from leu, that substance is beta hydroxy beta
metyl glutaryl coA ( HMG coA) ito ay intemediate sa cholesterol synthesis.
o pwede mong ilink yung protein to lipid metab through HMG coA because you can produce a
substance from leu that is actually use for lipid metab.
o there one inborn error na associated sa leu alone. deficiency of isovaleryl coA
dehydrogenase. such that isovaleric acid accumulates. you call it isovaleric acidemia. wala
yung enzyme na mag coconvert ng isovaleryl coA to HMG coA. accumulation of isovaleric
acid and this lead to cheesy odor of the breath and urine.
LYSINE
Lysine
Inborn error
o Hyperlysenemia
Accumulation of Lysine
Deficiency in the Saccharopine dehydrogenase
Arginase inhibited
Urea Cycle stops
Causes hyperammonemia
Ammonia intoxication
EXPLANATION:
Another essential amino acid proceeds to formation of sacaropene and fibecolic acid
There is one inborn error associated with lys. that is deficiency of sacaropene dehydrogenase.
if this enzyme is deficient, mag aacumulate yung lys at ang tawag ay hyperlysinemia in this inborn
error, high levels of lys inhibits the enzyme arginase
if the arginase is inhibited = ammonia accumulates. hyperlysinemia can also lead to
hyperammonemia.
THREONINE
Threonine Glycine
EXPLANATION:
Can be converted to gly. This is another example of a non essential amino acid being derived from
an essential amino acid.
LEMF and JEIF

METHIONINE
Methionine cysteine
o Homocysteine formed before cysteine
o Vitamin B6
Causes the conversion of Homocysteine to cysteine
o EXPLANATION:
o The catabolism of methionine proceeds to formation SAM (S-adenicil methionine ?)
o this is the active methyl donor of the body. pagkadonate ng methyl group
o examples of methylation reactions where you need a methyl group ----- conversion of
norepinephrine to epinephrine.
o you also need a methyl group to produce creatine as well as to produce choline.
o the catabolism of met proceeds to formation of cys ( isa nanamang halimbawa ng non
essential being derived from essential ).
o but in the conversion of met to cys, you pass through the formation of homocysteine.
usually nacoconvert agad yung homocysteine to cysteine basta dapat sufficient yung b6 mo.
INBORN ERRORS
o HOMOCYSTINURIA
Deficiency of cystathionine synthetase
Homocysteine not converted to cysteine
Homocysteine
o Corrosive of long living proteins
o Inhibits and degrades the structural components of arteries:
Collagen
Elastin
Proteoglycans
Accumulation of Homocysteine
Destroys blood vessel wall lining
Wall becomes rough
Cholesterol easily attached to the wall
Causes Hypertension and atherosclerosis in young people
If with Hypertension:
o Check if Homocysteine level is normal
o Lowering of Homocyteine
Give Vitamin B6
Vitamin B9, Folic Acid, Vitamin B12
Convers Homocysteine to Methionine
Methionine not converted to Homocysteine
No homocysteine
Happy lahat
Vitamin B12
Cannot be taken in large amount
Destroys the liver
EXPLANATION:
homocystinuria - deficiency of cystathionine synthetase
if this enzyme is deficient, you cannot convert homocysteine to cys.
LEMF and JEIF

you are going to accumulate homocysteine. accumulation of homocysteine will

destroy the lining of blood vessel wall.
pag nasira yung lining ng blood vessel wall, magiging rough yun, ay dapat nga diba
smooth ang lining ng blood vessel wall mo.
madali kang mag atherosclerosis.
Hypertension in young people.
how to lower homocysteine. you can make the conversion of homocysteine to
cysteine faster.
you should take high dose of vitamin b6 ... kaya lang kadalasan,,,, pag nag
accumulate yung homocysteine there is an accompanying deficiency of the enzyme
cysthathionine synthetase, kung meron kang deficiency ng enzyme na to, even if you
give large doses of B6, you will not be able to convert homocysteine to cys. so paano
mo nga mapapababa yung homocysteine level?
you give 2 vitamins that can convert homocysteine back to methionine.
etong dalawang bitamina na to ay vit. B9 at vit. B12. this is the reaso why for
younger people with HPN, aside from anti hypertensive drug, you give folic acid 400
mg, and high dose of vitamin b12 500 micrograms.
among all the vitamin B complex ... vit. b12 lang ang nag aaccumulate sa liver....
pag ng accumulate yun = toxic
o CYSTATHIONUNURIA
Deficiency of Cystathionase
Cannot convert methionine to cysteine
EXPLANATION:
Another inborn error is cysthathioninuria ( check nyo kung tama ) deficiency of the
enzyme CYSTHATHIONASE. just the same, you cannot convert met to cys.
This is the action of homocysteine, it degrades and inhibits formation of
collagen,elastin, and proteoglycans ( 3 main structural components of the artery ).
( ang homocysteine ay corrosive off different proteins)
CYSTEINE
Cysteine Pyruvate
Inborn
o Cystenuria
Renal transport defect
Accumulation of cysteine crystals cysteine stone
o Cystenosis
Formation of stones
Renal failure
GLYCINE
Simplest
Major Route
o Glycine Synthase pathway
Glycine +NAD + FH2
o Conversion to serine
By serine hydroxymethyl transferase
CANNOT INCONVERT
LEMF and JEIF

If one is Essential AA
CAN CONVERT if
If both non-essential AA
Functions:
o Heme Syntheis (+Succinyl COA)
o Source of C4, C5, N7 of purine ring
o Component of Glutathione
o Formation of Bile Salt (Glycocolic Acid
Absorption of lipids
o Conjugation with benzoic acid hippuric acid
Detoxification of benzoic acid
Detoxification mechanism
BIOSYNTHESIS OF NUTRIONALLY NON ESSENTIAL AMINO ACIDS
Glutamate
o From alpha keto glutarate
Add amino group
Glutamyl dehydrogenase
o Trans amination
Alpha keto glutarate undergoes transamination
Produces glutamate
Histidine figlu --? Glutamic Acid
Arginine
Glutamine
o Glutamate gluytamine
Glutamine synthetase
Aspartic Acid
o Oxaloacetate Aspartic Acid
Alanine
o Pyruvate Alanine
o Tryptophan alanine
Serine
o 3-Phosphoglycerate (glycolysis) , serine
o glycine serine
with Folic Acid
Serine hydroxymethy transfersae
o Glycine synthase pathway
o Break down of threonine
o Glyoxylate glycine
o Choline glycine
Proline
o Glutamate Proline (interconvertable)
Cysteine
o Methionine cysteine
Tyrosine
o Phenyalanine Tyrosine
SUMMARY of the SYNTHESIS OF NONESSENTIAL AA
Glycine Serine *
Proline Glutamic Acid *
Arginine Glutamic Acid
LEMF and JEIF
His Glu
Trp Ala
Phe Tyr
Thr Gly
Met Cys
Asp asn*
Glu gln
Pyruvate ala *
Oxaloacetate asp *
Alpha keto glutarate glu *
3 phosphoglycerate serine
* -- irreversible
IMPORTANT SUBSTANCE FROM AA
Glycine
o Bile salts
Glycocolic Acid
Glycocheno?
o Hippuric Acid
+ benzoic acid
o Creatine
3 AA for Creatine synthesis
Gly
Arg
Met
Step 1
Trans aminidation
o Gly + Arg = Guanido acetate (glycocyamine) + Ornithine
Amino group in Arg goes to Gly guanido acetate
Step 2
Guanido acetate + methy group (from SAM)
Forms creatine
Creatine
Can be converted to:
o Creatine Phosphate
Phosporylation rxn
o Creatinine
Dehyrdartion rxn
o Porphyrins
+ succinyl COA
Alanine
o COA
o Carnosine and Anserine
Related to Myosin ATPase
Enhances Copper Uptake
Serine, Theronine, Tyrosine
o Phosphorylation reactions:
Phosphoserine
Methionine
o Polyamines:
LEMF and JEIF

Spermidine
Spermine
o Norepinephrine Epinephrine
o Creatinine Phosphate
o Choline
o Carnitine
+ Lysine
Cysteine
o COA
Thioethanolamine portion of COA
o Taurine
+ bile acids
forms bile salts
example:
taurocholate
taurochenodeoycholate
o Cystine
Proteins with disulfide bonds
Histidine
o Histamine
Decarboxylation of histidine
vasodilator
o Ergothioneine
o Carnosine
o Anserine
Arginine
o Nitric Oxide
Neurotransmitter
Smooth muscle relaxant
Vasodilator
Opposite reaction of serotonin
o Creatinine
o Putrescine
o Spermidine
o Spermine
Tyrosine
o Melanin
o T3 T4
o Norepi epi
Glutamic Acid
o GABA
Tryptophan
o Serotonin
o Melatonin
o Niacin
o Indole and Skatole
GLUCOSE ALANINE CYLE
Glucose alanine
Alanine glucose
Alanine can easily converted to glucose
LEMF and JEIF

Helps maintain blood sugar level during fasting
NITROGEN BALANCE
Nitrogen In = Nitrogen Out

Nitrogen In > Nitrogen Out
o Positive Nitrogen Balance
o Protein retained and not utilized
o Causes:
Growth
Pregnancy
Convalescencing
Nitrogen in < Nitrogen Out
o Negative Nitrogen Balance
o Cause:
Metabolic stress
Low quality of food
Starvation / Malnutrition
Zero Intake, High Catabolism
NAP TRANS
Cysteine
Inborn error
Cystinuria
Due to renal transport defect that leads to formation of cysteine calculi.
Cystinosis
Also leads to formation of cysteine stones eventually causing renal failure.
Glycine
Simplest among the amino acid but has more functions than the other AA
The major role for the breakdown of Glycine is through the glycine synthase pathway. Glycine
carbon dioxide, ammonia, NADH,. You can also convert glycine to serine (interconversion) serine back to
glycine. Pwede mag interconvert only if the source is another non essential. Kung parehong non essential
pwedeng interconvertible, but you cannot interconvert if the amino acid comes from essential.
The keto acid derive from glycine is called glyoxylic acid.
Different functions
Heme synthesis (Glycine + succinyl CoA)
Source of C4,C5, and n7 in the purine ring
Component of glutathione together with cystein and glutamic acid
You can form bile salts from glycine conjugated with cholic acid = bile salts is for the
absorption of lipids.
You can conjugate it with benzoic acid to form hippuric acid = one way in detoxifying benzoic
acid in your body. Benzoic acid is a toxic substance that you derive from vegetables. Benzoic acid causes
abdominal pain, diarrhea and vomiting. Everytime you eat fruits and vegetables you dont develop
diarrhea, abdominal pain, and vomiting because the benzoic acid combines with the glycine and is now
converted to hippuric acid and that is no longer toxic.
Component of creatine together with arginine and methionine
LEMF and JEIF

Summarization:
o Glutamic acid.
You can synthesize it from alpha ketoglutarate just add an amino group through
glutamate dehydrogenase
Transamination with alpha ketoglutarate as the amino acid acceptor. Basta yung
tumatangap ng amino group ay alpha ketoglutarate lagi kang mag foform ng
Glutamic acid
Catabolism of histidine passed through FIGLU and that will also give you glutamic
acid
Argnine passing through ornithine can also give you glutamic acid
Proline and Glutamic acid are interconvertible: both are non essential amino acid
o Glutamine
You can synthesize it by adding ammonia to glutamic acid through the enzyme
glutamine synthetase. ito yung kung pano tayo mag detoxify ng ammonia sa
brain.
o Aspartic acid
Can be derived it from oxaloacetate ( kasi ito yung keto acid ng aspartic acid) just
add an amino group through transamination
o Asparagine
Can be derived from aspartic acid
o Alanine
Pyruvate( keto acid) + amino group = alanine
Catabolism of Tryptophan can also give you alanine
o Serine
Major source: 3-phosphoglycerate (intermediate of glycolysis)
o Can easily be converted to Serine
You can also get serine from glycine through interconversion, you must have folic
acid as the co enzyme plus serine hydorxy methyl transferase
o Glycine
Can be synthesize through Glycine synthase pathway
You can get glycine through breakdown of threonine
Glyoxylic acid + amino group = glycine (transamination)
Choline - because glycine is a component of choline
o Proline
You can get it from glutamic acid interconvertibe silang dalawa
o Cysteine
You can get it from methionine
o Tyrosine
Can be derived from phenylalanine
Glycine Serine
Proline Glutamic acid
Arginine glutamic acid
Histidine Glutamic acid
Tryptophan Alanine
Phenylalanine Tyrosine
Threonine Glycine
Methionine Cysteine
Aspartic acid Asparagine
LEMF and JEIF
Glutamic acid Glutamine

Pyruvate Alanine
Oxaloacetate Aspartic acid
Alpha ketoglutarate Glutamic acid
3-phosphoglycerate serine
Mga importanteng substances that can be derived from each amino acid
Special products that derived from the amino acid
o Glycine
Bile salt important for lipid digestion and absorption
2 types:
o Glycocolic acid
o Glycochelodeoxycholic acid
Hippuric acid this is the outcome when you conjugate it to benzoic acid
Product of detoxifying mechanism which happens in the liver.
Creatine
Glycine arginine and methionine you need this three for the creatine
synthesis
1st reaction of creatine synthesis: transaminidation- in contrast to
transamination, pag transamination ung alpha amino group yung tinatransfer.
Kapag transaminidation ang nililipat na amino acid yung nsa R-group
arginine + glycine = guanido acetate
o What amino acids have an amino group at the R position? ONLY the
BASIC (arginine, histidine and glycine)
*** kakabit yung amino group ng arginie yung nasa R position which is called
guanido to glycine, so glycine is called guanido acetate
2nd reaction: trans methylation mag lilipat ka ngayon ng methyl group, with
the methyl group provided by s-adenosyl methionine (SAM)
o Yung guanido acetate dadagdagan mo ng methyl group through SAM =
creatine
Creatine can be converted to creatinine by a dehydration step or you can

convert creatine to creatine phosphate which is a high energy compound
through phosphorylation reaction.
Porphyrins
Glycine + Succinyl CoA
C4, C5, and N7 of the purine comes from glycine
o Alanine
Co enzyme A requires alanine
Carnosine and anserine requires beta alanine and histidine
these two are related to myosin atpase further activation and enhance copper
uptake
o Serine, Threonine, Tyrosine

Phosphorelation reaction . you can convert them to phosphoserine ,
phosphothreonine and phosphotyrosine this is important for activation and
inactivation of enzyme
o Methionine
LEMF and JEIF

Spermadine and Spermin

These are amines derived from methionine
They stabilize intact cells
They have hypotensive properties
You need methionine for creatine synthesis as well as the synthesis of choline
Needed also for synthesis of carnitine together with lysine
Carnitine is important for your beta oxidative pathway/ carrier of long chain
fatty acids
o Cysteine
Also component of Co enzyme A
Source of taurine
Bakit may taurine sa gatas?
o Taurine can become bile salt and bile salt is needed for lipid absorption
and lipids is needed for brain development together with proteins.
o Histidine
Histidine histamine
The substance release whenever you have allergies
Allergies is more then rashes!!! That is very minor reaction to histamine ang
pinaka MAJOR? Ay yung pag nag bronchoconstrict ka. If that happens para
kang sinakal hindi ka mkakahinga or a sudden dilatation of your blood vessel
so BP drops suddenly and then you drop suddenly also = anaphylactic
shock!!!
o Arginine
Nitric oxide you can derive this from arginine
A neurotransmitter
Smooth muscle relaxant and a vasodilator
Kabaligtaran ito ng serotonin - smooth muscle contractor, vaso
Needed for creatine synthesis as well as synthesis of putresine, spermidine, and
spermin
o Tyrosine
T3 and t4
Nor epinephrine and epinephrine
You also need SAM to convert nor epinephrine to epinephrine
melanine
o Glutamic acid
Gaba Natural tranquilizer
Without gaba you are going into convulsive seizures
o Tryptophan
Serotonin
Melatonin
Indolence katole
Niacin
o Glucose alanine cycle

This shows you that alanin can be easily converted to glucose
*** when all your glycogen reserve you used up all you fat deposits you will now use
now muscle protein, the alanin that you get from the muscle protein goes back to the
liver it will undergo gluconeogenesis so you get back glucose out of it. That glucose
will go back to the blood to help maintain the blood sugar level. This is a cycle that
helps maintain your blood sugar level during the times you are not eating
o Nitrogen balance
LEMF and JEIF
o Normally your intake of protein should be equal to output

o Nitrogen in = nitrogen out
o Whatever tissue proteins are synthesized this is balanced by the amount of tissue proteins
that are catabolized yan yung protein turnover, dapat pantay pantay yan!
o If there is nitrogen in > nitrogen out that is positive nitrogen balance you retain most of the
protein, niretain mo hindi na catabolize
This occur when you are still growing kasi growth means more cells and tissues
Lactating kasi another human being is being form
Convalescing or recuperating from an illness because you have to repair a worn out
tissue
o If there is nitrogen in < nitrogen out negative nitrogen balance
Catabolizing at a faster rate due to metabolic stress or you are suffering prolong
illness o yung kinakain mo eh low quality meaning you lack essential amino acid, pag
lack ang essential amino acid hindi ma synthesize yung kailangan ng katawan mo or
wala ka tlgang protein sa diet/ starvation
o *** if you dont eat it doesnt mean catabolism stop, your usual catabolism goes on. Pwede zero
ang intake pero catabolism still goes on.
LEMF and JEIF

Biochem Trans - Protein Metab (LECTURE)

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Biochem Trans - Protein Metab (LECTURE)

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Biochemistry Protein and Amino Acid Metabolism

Dr. Santos Nov. 15, 2012

PATHWAYS THAT DEGRADED PROTEINS

SOURCES OF AMINO ACID

LEMF and JEIF

AMINO ACID POOL

PROTEIN DIGESTION and ABSORPTION

LEMF and JEIF

LIVER in AMINO ACID METABOLISM

CLASSIFICATION OF AMINO ACIDS

ESSENTIAL AMINO ACIDS

LEMF and JEIF

NON ESSENTIAL AMINO ACIDS

ENZYMES USED IN AMINO ACID BIOSYNTHESIS

AMINO ACID CATABOLISM

Removal of the alpha-NH2 group

LEMF and JEIF

o 3 WAYS OF THE REMOVAL of the ALPHA-NH2 GROUP

o L-Amino Acid Oxidase

o D-Amino Acid Oxidase

Zellweger Cerebrohepatorenal Syndrome (CHRS)

LEMF and JEIF

One Carbon Transfer

WAYS OF DETOXIFYING AMMONIA

Reversal of Glutamate Dehydrogenase Reaction

o Glutamine goes to the kidneys Glutamic Acid + NH3

o UREA CYCLE (Krebs Heseleit Cycle)

CPS 1 vs. CPS 2 (Carbamoyl Phosphate Synthetase)

ENZYMES IN THE UREA CYCLE:

RATE LIMITNG STEPS

LEMF and JEIF

CLINICAL CORRELATION (yes may clinical correlation na sa biochem)

CONGENITAL ANOMALIES in the UREA CYCLE

AMMONIA INTOXICATION in LIVER DISEASE

Krebs cycle will NOT produce ATP

THERAPHY for UREA CYCLE DEFICIENCY

METABOLIC FATES OF KETO ACIDS

CATABOLIC DISPOSITION OF CARBON CHAINS OF AMINO ACIDS

Amino Acids can:

METABOLIC PATHAWAY of PHENYLALANINE and TYROSINE

SUBSTANCE DERIVED FROM PHE and TYR:

Also KYNURERINE ANTHRANILATE PATHWAY

Trp load test

LEMF and JEIF

o BLUE DIAPER SYNDROME

Histidine urocanic Acid Glutamic Acid alpha keto glutarate

VALINE, LEUCINE, ISOLEUCINE

Not metabolized in the liver, brain and muscle

Isoleucine keto acid: a-

o tong PKU at MSUD ay kasama sa new born screening.

LEMF and JEIF

LEMF and JEIF

you are going to accumulate homocysteine. accumulation of homocysteine will

LEMF and JEIF

BIOSYNTHESIS OF NUTRIONALLY NON ESSENTIAL AMINO ACIDS

SUMMARY of the SYNTHESIS OF NONESSENTIAL AA

IMPORTANT SUBSTANCE FROM AA

LEMF and JEIF

GLUCOSE ALANINE CYLE

LEMF and JEIF

Helps maintain blood sugar level during fasting

Nitrogen In = Nitrogen Out

LEMF and JEIF

Glutamic acid Glutamine