CHAPTER Major Metabolic

Pathways of Glucose
9
lactose
leads to
ii. Deficiency
of lactase
CHAPTER ATA GLANCE intolerance. In this condition, lactose accumu-
on lates in the gut.
Irritant d i a r r n e a and flatulence
able to answer questions
The reader will be
the following topics. are seen.
1. Digestion of cartbohydrates ii. There may
be congenital (primary) or acquired
trans- causes. AS age advances, lactase
of glucose and glucose (secondary)
2. Absorption Another reason for
will be lost.
porters enzyme
regulation lactose i n t o l e r a n c e may be sudden
3. Glycolysis pathway its and acquired
4. Energy yield from giycolysIS milk based diet. Lactase is an
change into a
If milk 1s withdrawn
5. Cori's cycle inducible enzyme.
a junction point diarrhoea will be limited. Curd
6. Pyruvate as temporarily, the
7. Gluconeogenesis and
Malate shuttle
is also an effective
treatment, because the
8. Glucose alanine cycle contains the enzyme
lactobacili present in curd
of glycogen in yeast,
9. GycogenolysiIs, degradation lactase. Lactase is abundantly seen
10. Glycogenesis, gycogen synthesis used in treatment.
metabolism, which couid aiso be
11. Regulation of glycogen
Cyclic AMP
ABSORPTION AsOHYDRATES
diseases
12. Glycogen storage nonosac665 are absorbed by the
Onty
ntosisa s 0rGE s maximum tor galactose,
or minimum tor tructose.
DIGESTION OF CARBOHYDRATES
oaeta e
are present as conmpiex
1. In the diet carbohydrates and to Abs3hofs o e
polysaccharides (starch, glycogen), and Glucose has spocih transporters, which are
minor extent, as disaccharides (sucrOSe transmembrane proleins. Table 9.1 showsa
lactose). They are hydrolysed to mono
saccharide units in the gastrointesuru u u summary of the glucose transporters
easier.
makes the digestion process
Cooking 1. Co-transport from Lumen to Intestinal cel
ii. This process of digestion starts in mouth by i. This process is mediated by Sodium Dependent
the salivary alpha-amylase.in However, tne
for digestion the mouth is Glucose Transporter-1 (SGluT-1) (Fig. 9.1)
time availlable acid AbSorption from intestinal lumen into intestinai
limited, because the gastric hydrochloric
sallvary amylase.
of cell is by co-transport mechanism (secondaiy
will inhibit the action
11. In the pancreatic juice another alpha-amylase active transport) (Chapter 2).
the alpha-1,4 . Amembrane bound carrier protein is invoiveo
IS available which will hydrolyse
so a s to produce
9iycosidic linkages randomly, which carries glucose, along with sodium. 1his

Smaller Subunits like maltose, 1somaltose, sodium is later expelled by the sodium pum
dextrins and branched or unbranched oligo with utilization of energy. So energy is needeu

Saccharides.
v. The cells of brush border of intestine contain indirectly (details in Chapter 2).
tne enzymes, sucrase, maltase, isomaltase l . The transporter in intestine is named as SGlu

and lactase. They hydrolyse the corresponding 1 and the transporter in the kidney is calle
disaccharides into component monosaccha- SGluT-2. The first one is involved in glucos
rides which are then absorbed. galactose malabsorption. The SGlulz
Clinical Application; Lactose Intolerance defective in congenital renal glycosuria.
Lactase hydrolyses lactose to glucose and iv. Clinical application: Common treatment o
ns
diarrhea is oral rehydration fluid. lt conta
galactose. Lactase is present in the Drusn
border of enteroCytes. glucose and sodium. Presence of glucOS
 Chapter 9; Major Metabolic Pathways of Glucose 91
Table 9.1. Glucose time, the binding site is now exposed on the
transporters
inner side of the membrane, releasing the
ransporter Present in Properties The
process is called ping-pong
GluT1 RBC, brain, kidney, Glucose uptake in glucose.
colon, retina,
mechanism (Fig. 9.2A).
most of cells
iv. GluT2 (facilitated transport) is involved in
placenta
from blood stream to
GluT2 Serosal surface of Low affinity; glucose absorption of glucose
intestinal
cells. GluT2 is present in intestinal epithelial
cells, liver, uptake in liver;glucose and
beta cels of pancreas sensor in beta cells cells, liver cells, beta cells of pancreas
GluT3 Neurons, brain High affinity; glucose kidney.
into brain cells V. Since GluT2 has a high Km for glucose, its
presence in beta cells is ideally suited
for sensing
GluT4 Skeletal, heart Insulin mediated a high glucose level and releasing insulin (See
muscle, adipose tissue glucose uptake
the
Chapter 24). So this mechanism enables
GluTs Small intestine, Fructose transporter glucose level and
pancreas to monitor the
testis, sperms, poor ability to trans-
adjustthe rate of insulin secretion. Comparison
kidney port glucose
of SGluT and Glu2 is shown in Fig. 9.28,
GluT7 Liver endoplasmic Glucose from ER
reticulumn to cytoplasm
3. Glucose Transporter 4
SGluT Intestine, kidney Cotransport; from in
i. GluT4 is the major glucose transporter
Jumen mto cen skeletal muscle and adipose tissue (F1g. S.3).

oral rehydration fluid allows uptake of sodium

to replenish body sodium chloride. C n initestinai ceils

r a n s p o r t e r c h a n g e s direction

2. Another Uniport System Releases Sico Binding site

into Blood
.Thesame intestinal epitholial cels fa
mecharnism on t e mert-
different transpot
Intestinal
brane facing capillaries (Fig. 9.2A).
stream by the
cells release glucose into blood Glucose in
carrier mechanism called
Glucose Trans- blood stream
porter Type 2 (GluT2).
on sodium. Fig. 9.2A. Glucose absorption (Glu2)
i. This transporter is not dependent
It is a uniport, facilitated diffusion system.

i . Glucose binds to the transporter on one side

membrane. When fixed, the complex Basal surface
of the
This leads to the
changes configuration, ithe
Intestinal epitheial ceil R Blood
Site. At the same
closure of the first binding ntesuna
Na is expeued
ium
2 Na'e Pump
UCOse
(Na-K-ATPase)
Externor

L Glucose

SGlut Glu2

Cytosol
Fig. 9.2B. Intestinal absorption of glucose. At the
Fig.9.1. SGluT. Sodium and glucose co-transport intestinal lumen, absorption by SGluTand
side; sodium is then pumped out
is
blood vessel side, absorption is by GluT2
at the

system at luminal
 Section B: Genera
92 Textbook of Biochemistry:;
Glucose outside the cell

AR
Glucose inside the cell

Fig. 9.3. GluT4. Glucose transport in cells

ii. GluT4 is under the control of insulin. But other

glucose transporters are not under the control
of insulin.
ii. Clinical application: Insulin induces
the
movement of intracellular GluT4
moleCuies
the cell surface and thus increases
giueese
uptake. Type diabetes mellitus (Cspter
In 2
24), membrane GluT4 is reduced, leading
insulin resistance in muscle and fat te
cells.
diabetes, entry of glucose into muscle is only
In

half of normal cells.

 phorylds. nyPS
40,000 births.
10.4).
3. Bilirubin is less and bilirubin conjugation
uptake
bilirubin level is METABOLISM OF ALCOHOL
is reduced; so unconjugated
Alcohol absorption starts from the stomach itself,
increased in blood (for bilirubin, see Chapter 21).
and but most of it is absorbed by intestine. Only 1% of
4. There is enlargement of liver, jaundice
severe mental retardation. the ingested alcohol is excreted
fraction of the
through the lungs
alcohol is oxidized in
accumulates, leading to
or urine. Major
5. Free galactose liver.
excreted urine
in the
It is partly
galactosemia.
(galactosuria)
6. Galactose is reduced to dulcitol (See Chapter 6). 1. Alcohol Dehydrogenase (ADH)
dependent cytoplasmic enzyme that
The accumulation of dulcitol
in the
lens resuits S an NAD
This is called OXIdizes ethanol to acetaldehyde (Fig. 10.12).
in cataract due to its osmotic effect.

Alcohol dehydrogonaso Acetaldehyde Aldehyde dehydrosun Acetic acid

Ethanol
CHCHOH CH CHO CH-COOOH
NAD NADH H NAD NADH+ H

Fig. 10.12. Alcohol metabolism

122 Textbook of Biochemistry: Section B: General Metabolism

Alcohol
dehydrogenase is a dimer and has 6 iso- ili. Reduced oxaloacetate, decreased pyruvate
enzymes. In some individuals the enzyme is and high NADH level causes suppression gf
mutated. This mutation rate is more in Orientals. In TCA cycle. So Acetyl COA is acCumulater
such individuals, alcohol metabolism is slower and which favors ketogenesis.
even small quantity of alcohol iv. Increased level of acetyi COA Causes increased
may produce
symptoms of intoxication. The enzyme was fatty acid synthesis, Dut tatty acid is not
identified by Bateilli and Stern in 1909. oxidized. So fat is accumulated in liver
resulting in fatty liver and steatosis.
2. Aldehyde Dehydrogenase v. Alcohol also increases the release of ROS
Acetaldehyde is further oxidized to acetate by a leading to mitochondrial damage and apoptosis
mitochondrial NAD dependent enzyme (Fig. vi. Lactic acidosis causes decreased excretion of
10.12). The acetate iIs then converted to acetyl COA. uric acid, resulting in acute attack of gout (See
The activity of alcohol dehydrogenase is more than
Chapter 39).
aldehyde dehydrogenase. So acetaldehyde vi. Alcohol causes CNS
accumulates in liver. Aldehyde is toxic, which in
depression by inhibiting
excitatory receptors (N-methyl aspartate
excess may lead to cell death. The activity of
aldehyde dehydrogenase is less in indians, when
receptors) and by potentiating inhibitory
neurotransmitter (GABA) receptors.
compared to Europeans.
Chronic Alcohri
Ethanol Oxidizing System
3. Microsomal
(MEOS)
A.fACCumUlatot
Alcohellsm ta

st
ap

7er cells leading to fatty

It is another mechanism of detoxification of alcohol.
It is cytochrome P450 dependent and is inducible.
iver.Actee effect ofacetaldehyde
leads to cettitec0
This accounts for metabolic tolerance of alcohol ii. This is followe
placement by tibrous
observed in chronic alcoholics. tissue. FiDrosi Ver is called Cirrhosis
Ethanol can be oxidized in liver microsomes to
When liver functions are reduced (See
acetaldehyde by a mixed function oxidase. The electron donors
are ethanol and NADPH by which O is reduced to water. chapter 26) hepaic coma results.
.
CH-CHOH NADPH+ H+20 Elimination rates of ethanol vary among individuals and
CH,CHO+ 2H,02 + NADP+ populations. Susceptibility to alcohol is a compler
Tunction of genetics and socioeconomic factors
MEOS is part of the superfamily of cytochrome P450, all
Possession of an alele that encodes a relatively tast
of which catalyze similar reactions. About 10 gene families
ADH (alconol dehydro-genase) is associated wilh
and 100 different cytochrome P450 molecules are available. ereased susceptibility. A single amino acid substitubo
The isoenzyme with highest activity towards ethanol is
(Glu487 by Lys) produces a AL DH (Aldehyde
designated CYP2E1 (2 relers to the gene family, E refers to denydrogenase) with high Km (260 times) an
he subtarmily and 1 relers to the
particular enzyme), CYP2E1 alfinity for acetaldehyde. Vmax is also reduced 10 e
nas higher Km for ethanol than Class 1 ADH (11 mM). When This enzyme is very inactive. omozygotes for tha
the ethanol consumption is high, higher proportion is
rant afford absoluto Homoyg ism
metabolized by MEOS. Other CYP 1s0enzymes also * ve per cent of all deth against aiconou
n india are due to liv
metabolize alcohol and MEOS refers to the combined oxidizing ch th
s
diseases, 1or which the most alcoho
important
activity of all these. In india, chronic alcoholism is the mostcuiprn
TOr
morbidity and co leadinsThe
activity of mitochonria oSs of man hours
Biochemical Alterations in Alcoholism mitochondrial
aldehyde
Both the oxidation steps of alcohol produces NADH, n Aslans compared to westerndehydrogen
population. h
ance
ndians are more
resulting in a high NADHINAD ratio. As a result, prone for alcoholic cirnoss
several metabolic adaptations occur. B. Alcoholism and Nervous
i. In the cytoplasm, the high NADH level favors n
chronic alcoholics, System
the brain ventricles
conversion of pyruvate to lactate, leading to enlarged, neurons are
lost, neuro-degeneral
lactic acidosis.

eads
Changes set in the memory is affected. In O n o l i c s

ii. Deficieny valoacetate.

to
inadequate Combined thiamine deficiency leads to acks
This results in
disease. Aldehyde Wern ale
giuconeogenesIs, leading to hence inhibits pyridoxal phosce
depression of neuritis is very common
hypoglycemia. Chapter 34). in alcoholic
 CHAPTER General Amino Acid
14 Metabolism
(Urea Cycle, One Carbon
Metabolism)
CHAPTERATA GLANCE the diet or
synthesized in the
body. The
amino acids areobtained trom the diet. sentia
The reader will be able
to answer questions on the one is deficient, Even
protein synthesiS cannot take plars
following topics: The body amino acId pool always in
1. Digestion of proteins
is a dyname
steady state. In an aduit, the rale of synthesis
2. Absorption of acids
amino
proteins balances the rate of degradation, so tha
3. Meister cycle nitrogen balance is maintained (Fig. 14.1)
4. Cathepsins, proteasomes
5. Inter-organ transport of amino acids DIGESTION OF PROTEINS
The dietary proteins are denatured on
6. Transamination and trans-deamination cooking and
therefore more easily digested. All these
7. Formation of ammonia enzymes
8. Urea cycle
are hydrolases (Class 3 enzymes) in nature
Proteolytic enzymes are secreted as inactive
9. Urea cycle disorders
zymogens which are converted to their active form
10. Urea level in blood
in the intestinal lumen. This would prevent auto-
11. One carbon metabolism
digestion of the secretory acini. The proteolytic
NZymes include:
. Endopeptidases. They act on peptide bonds
The main role of amino acids is in the syntresis inside the protein molecule, so that the protein
structural and functional proteins. Unika becomes successively smaller and smaller
carbohydrates and fats, there is no storage form of units. This group includes Pepsin, Trypsin
proteins in the body. A 70 kg man has an average Chymotrypsin, and Elastase.
protein turnover rate of 400 g per day (same amount 2. Exopeptidases, which act at the peptide bond
synthesized and same amount broken down). The only at the end region of the chain. This group
non-essential amino acids are either derived from includes:

Keto acid Ammonia Urea (15-30 g/day)

etary proleins- Body
(50-75 glday)
amino
cid pool
(100 9) Oxidation>Energy

Breakdown of Gluconeogenesis
body proteins
(300-400 9/day)
Nonessential amino acids

Synthesis of body protoins Synthesis of specialized products

(300-400 g/day)
(heme, purines, pyrimidines,
creatine, enzymes, hormones, etc)

Fig. 14.1. Overview of metabolism of amino acids

 Chapter 14; General Amino Acid Metabolism (Urea Cycle, One Carbon Metabolism)11
PROTEASES Table 14.1. Action of proteolytic enzymes

Enzyme Hydrolysis of bonds formed

Exopeptidases Endopeptidases O-O-O-O- by carboxyl groupsof

Aminopeptidases e#o-O-O-o Phe, Tyr, Trp, Met

Pepsin
Dipeptidyl peptidases -0-0-Op Trypsin Arg, Lys
Tripeptidyl peptidases ---0-O Phe, Tyr, Trp, val, Leu
Chymotrypsin
Ala, Gly, Ser
Carboxypeptidases -O-O-0- Elastase
Carboxypeptidase AC-terminal aromatic amino acid
Peptidyl dipeptidases O-0-0--
C-terminal basic amino acid
Carboxypeptidase B
Dpeptidases
Tripeptidases -0-o
Milk protein, casein
Omega peptidases (Box 14.1). It is absent in adults.
O-O-0-0- is converted to paracasein by the
action of rennin.
--0-O-O further by
This denatured protein is easily digested
Fig. 14.2. Action of proteases. The enzyme pepsin.
hydrolyses the peptide bond at the site of arrow
2. Pepsin as inactive
2-A. Carboxypeptidase acts on the peptide It is secreted by the chief cells of stomach
of pepsinogen to
bond only at the carboxy terminal end on pepsinogen. The conversion
removal of 44 amino
the chain pepsin is brought about by
iCh acts on the acids from the N-terminal end, by the hydrochloric
2-B. Aminopett is around
terminal acid. The optimum pH for activity of pepsin
peptide br a Ehg amiri0
2. Pepsin is an endopeptidase, (Table 14.1). Pepsin
end on U r
bonds formed by
GS
13 ovm in Figure catalyses hydrolysis of the
A summary of thet by carboxyl groups of Phe, Tyr, Trp and Met. By the
9 0 C n is elfected
14.2. The digestio9 action of pepsin, proteins are broken into proteoses
enzymes in:
and peptones.
A. Stomach
B. Pancreas and B. Pancreatic Digestion of Proteins
C. Intestinal cells The optimum pH for the activity of pancreatic
the alkaline bile and
enzymes (pH 8) is provided by
A. Gastric Digestion of Proteins is
acid is secreted pancreatiC Juice. Ihe secretion of pancreatic juice
In the stomach, hydrochloric the peptide hormones, Cholecysto-
optimum tor the Stimulated by
(Chapter 26). It makes the pH Kinin and Pancreozymin.
activates pepSin. Ihe
action of pepsin and also Pancreatic juice contains the important endo-
acid also denatures the proteins.
peptidases, namely Trypsin, Chymotrypsin,
Elastase and Carboxypeptidase.
1. Rennin
is active in These enzymes are also secreted as
Rennin otherwise called Chymosin, zymogens
curdling of milk. (trypsinogen, chymotrypsinogen and pro-elastase),
mants and is involved in the
so that the pancreatic acinar cells are not
Renin are Different
Box 14.1. Rennin and autolysed. All the three are serine proteases, i.e.
in
is the proteolytic enzyme
present the active centers of these enzymes contain serine
Kennin
gastric juice. residues
is proteolytic enzyme, secreted by
Nenin the activation of 3. Trypsin
Idneys. It is involved in
a hypertensive Trypsinogen is activated by enterokinase (entero
to angiotensin,
anglotensinogen
agent. peptidase) present on the intestinal microvillus
 B: General Metabolism
172 Textbook of Biochemistry: Section
membranes. Once activated, the trypsin activates 6. Leucine aminopeptidase
Trypsin is activated by the t releases the N-terminal basic amino acids ane
other enzyme molecules.
removal of a hexapeptide from N-terminal end. glycine.
the bonds formed
Trypsin catalyses hydrolysis of
and Lys. 7. Proline amino peptidase
by carboxyl groups Arg
of
Acute pancreatitis: Premature activation of It removes proline from the end of polypeptidee
trypsinogen inside tne pancreas itself will result in
the autodigestion of pancreatic cells. The result is 8. Dipeptidases and tripeptidases
acute pancreatitis. It is a life-threatening condition. They will bring about the complete digestiona
proteins, their specificities are shown in Figure 14
4. Chymotrypsin
Trypsin will act on chymotrypsinogen, in such a ABSORPTION OF AMINO ACIDS
are formed. These
manner thatA, and peptides so that the active
B C
are approximated,
ne absorption of amino acids occurs mainu
3 segments the small intestine. It is an energy
site is formed. Thus, selective proteolysis produces requiring
the catalytic site. process. These transport systems are carrie
mediated and or ATP sodium dependent sympor
5. Carboxypeptidases systems. There are 5 different carriers for amino
the proteins into
Trypsin and chymotrypsin degrade acids:
small peptides, these are further hydrolysed intO
, Neutral amino acids (Alanine, Valine, Leucine
dipeptides and tripeptides by carboxypeptidases
present in the pancreatic juice. The procarboxy Methionine, Phenylalanine, Tyrosine, Isoleucine
Besic amino acids (Lys, Arg) and Cysteine
peptidase is activated by trypsin.. They are metailo 3mna ackds and Glycine
enzymes requiring zinc.
N N 0 acids (Asp, Glu)
C. Intestinal Digestion of Proteins R 7 2cids (beta alanine).
Complete digestion of the small peptides to the ievei

of amino acids is brought about by enzymeS presernt e E e ETnma Glutamyl Cycle)

inintestinal juice (succus entericus). The luminal an y tubules and brain, the absorption df neura
Surtaceof intestinal epithelial cell contains the a d s 3ected by the gamma glutamyl cycle. TIheman
roie is piayati by the tripeptide glutathione (GSH) (gammu
following enzymes:

Amino acid (outside membrane)

Transferase (gamma-glutamyl transpeptidaso) MEMBRANE ee

(nside membrane)

Glutathione
Cysteinyl glycine
Glutamyl amino acid
(gamma-glutamy
ysteinyl-gycine) Glycine Cysteine
Amino acid (inside cell)

ADP
Oxoproline
ATP

Glutamyl-cysteine ATP
JGlutamate ADP
ATP

gamma-glutamyl transforase; 2 gamma-glutamyl cyclotransferase; 3 5-oxoprolinase;

4
gamima-glutamyl cysteine synthetase; 5 glutathione synthetase

Fig. 14.3. Gamma glutamyl cycle (Meister cycle)